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According to the latest reports from WHO, the incidence of antibiotic-resistant bacterial infections is increasing worldwide, resulting in increased morbidity and mortality and a rising pressure on health-care systems. However, the development of new antibiotics is an expensive and time-consuming process, urging scientists to seek alternative antimicrobial strategies. Over the past few decades, the concept of therapeutic administration of bacteriophages (also known as phages) has gained popularity worldwide. Although conceptually promising, the widespread implementation of phage therapy in routine clinical practice is restricted by the scarcity of safety and efficacy data obtained according to the strict standards of the applicable clinical trial regulations. In this systematic review, we list clinical data published between Jan 1, 2000 and Aug 14, 2021 on the safety and efficacy of phage therapy for difficult-to-treat bacterial infections, and provide an overview of trials and case studies on the use of phage therapy in several medical disciplines.

Effective dosing of isavuconazole in patients supported by extracorporeal membrane oxygenation (ECMO) is important due to the role of isavuconazole as a first-line treatment in patients with influenza- and COVID-19-associated pulmonary aspergillosis. To date, robust pharmacokinetic data in patients supported by ECMO are limited. Therefore, it is unknown whether ECMO independently impacts isavuconazole exposure. We measured isavuconazole plasma concentrations in two patients supported by ECMO and estimated individual pharmacokinetic parameters using non-compartmental analysis and two previously published population pharmacokinetic models. Furthermore, a narrative literature review on isavuconazole exposure in adult patients receiving ECMO was performed. The 24 h areas under the concentration–time curve and trough concentrations of isavuconazole were lower in both patients compared with exposure values published before. In the literature, highly variable isavuconazole concentrations have been documented in patients with ECMO support. The independent effect of ECMO versus critical illness itself on isavuconazole exposure cannot be deduced from our and previously published (case) reports. Pending additional data, therapeutic drug monitoring is recommended in critically ill patients, regardless of ECMO support.

Can SARS-CoV-2 hitchhike on the olfactory projection and take a direct and short route from the nose into the brain? We reasoned that the neurotropic or neuroinvasive capacity of the virus, if it exists, should be most easily detectable in individuals who died in an acute phase of the infection. Here, we applied a postmortem bedside surgical procedure for the rapid procurement of tissue, blood, and cerebrospinal fluid samples from deceased COVID-19 patients infected with the Delta, Omicron BA.1, or Omicron BA.2 variants. Confocal imaging of sections stained with fluorescence RNAscope and immunohistochemistry afforded the light-microscopic visualization of extracellular SARS-CoV-2 virions in tissues. We failed to find evidence for viral invasion of the parenchyma of the olfactory bulb and the frontal lobe of the brain. Instead, we identified anatomical barriers at vulnerable interfaces, exemplified by perineurial olfactory nerve fibroblasts enwrapping olfactory axon fascicles in the lamina propria of the olfactory mucosa. ispartof: NEURON vol:110 issue:23 pages:3919-+ ispartof: location:United States status: published

Contains fulltext : 286888.pdf (Publisher’s version ) (Closed access) BACKGROUND: Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) affect about 15% of critically ill patients with influenza or COVID-19, respectively. These viral-fungal coinfections are difficult to diagnose and are associated with increased mortality, but data on their pathophysiology are scarce. We aimed to explore the role of lung epithelial and myeloid innate immunity in patients with IAPA or CAPA. METHODS: In this observational study, we retrospectively recruited patients who had been admitted to the intensive care unit (ICU) of University Hospitals Leuven, Belgium, requiring non-invasive or invasive ventilation because of severe influenza or COVID-19, with or without aspergillosis, between Jan 1, 2011, and March 31, 2021, whose bronchoalveolar lavage samples were available at the hospital biobank. Additionally, biobanked in vivo tracheobronchial biopsy samples from patients with IAPA or CAPA and invasive Aspergillus tracheobronchitis admitted to ICUs requiring invasive ventilation between the same dates were collected from University Hospitals Leuven, Hospital Network Antwerp (Belgium), and Amiens-Picardie University Hospital (France). We did nCounter gene expression analysis of 755 genes linked to myeloid innate immunity and protein analysis of 47 cytokines, chemokines, and growth factors on the bronchoalveolar lavage samples. Gene expression data were used to infer cell fractions by use of CIBERSORTx, to perform hypergeometric enrichment pathway analysis and gene set enrichment analysis, and to calculate pathway module scores for the IL-1β, TNF-α, type I IFN, and type II IFN (IFNγ) pathways. We did RNAScope targeting influenza virus or SARS-CoV-2 RNA and GeoMx spatial transcriptomics on the tracheobronchial biopsy samples. FINDINGS: Biobanked bronchoalveolar lavage samples were retrieved from 166 eligible patients, of whom 40 had IAPA, 52 had influenza without aspergillosis, 33 had CAPA, and 41 had COVID-19 without aspergillosis. We did nCounter gene expression analysis on bronchoalveolar lavage samples from 134 patients, protein analysis on samples from 162 patients, and both types of analysis on samples from 130 patients. We performed RNAScope and spatial transcriptomics on the tracheobronchial biopsy samples from two patients with IAPA plus invasive Aspergillus tracheobronchitis and two patients with CAPA plus invasive Aspergillus tracheobronchitis. We observed a downregulation of genes associated with antifungal effector functions in patients with IAPA and, to a lesser extent, in patients with CAPA. We found a downregulated expression of several genes encoding proteins with functions in the opsonisation, recognition, and killing of conidia in patients with IAPA versus influenza only and in patients with CAPA versus COVID-19 only. Several genes related to LC3-associated phagocytosis, autophagy, or both were differentially expressed. Patients with CAPA had significantly lower neutrophil cell fractions than did patients with COVID-19 only. Patients with IAPA or CAPA had downregulated IFNγ signalling compared with patients with influenza only or COVID-19 only, respectively. The concentrations of several fibrosis-related growth factors were significantly elevated in the bronchoalveolar lavage fluid from patients with IAPA versus influenza only and from patients with CAPA versus COVID-19 only. In one patient with CAPA, we visualised an active or very recent SARS-CoV-2 infection disrupting the epithelial barrier, facilitating tissue-invasive aspergillosis. INTERPRETATION: Our results reveal a three-level breach in antifungal immunity in IAPA and CAPA, affecting the integrity of the epithelial barrier, the capacity to phagocytise and kill Aspergillus spores, and the ability to destroy Aspergillus hyphae, which is mainly mediated by neutrophils. The potential of adjuvant IFNγ in the treatment of IAPA and CAPA should be investigated. FUNDING: Research Foundation Flanders, Coronafonds, the Max Planck Society, the Fundação para a Ciência e a Tecnologia, the European Regional Development Fund, "la Caixa" Foundation, and Horizon 2020.

Objectives Inappropriate prescribing of antimicrobials in hospitals contributes to the emergence of resistance and adverse drug events. To support antimicrobial stewardship (AMS), clinical decision rules focusing on antimicrobial therapy were implemented in the ‘Check of Medication Appropriateness’ (CMA). The CMA is a hospital-wide pharmacist-led medication review service consisting of a clinical rule-based screening for potentially inappropriate prescriptions (PIPs). We aimed to investigate the impact of the CMA on antimicrobial prescribing. Methods An interrupted time series study was performed at the University Hospitals Leuven. The pre-implementation cohort was exposed to standard-of-care AMS. Afterwards, an AMS-focused CMA comprising 41 specific clinical rules, targeting six AMS objectives, was implemented in the post-implementation period. A regression model was used to assess the impact of the intervention on the number of AMS-related residual PIPs between both periods. The total number of recommendations and acceptance rate was recorded for the 2 year post-implementation period. Results Pre-implementation, a median proportion of 75% (range: 33%–100%) residual PIPs per day was observed. After the CMA intervention, the proportion was reduced to 8% (range: 0%–33%) per day. Use of clinical rules resulted in an immediate relative reduction of 86.70% (P Conclusions We proved that the CMA approach reduced the number of AMS-related residual PIPs in a highly significant and sustained manner, with the potential to further expand the service to other AMS objectives.

S3.3 Innate immune responses to pathogenic fungi, September 21, 2022, 4:45 PM - 6:15 PM Objectives Up to 20% and 15% of critically ill influenza and coronavirus disease 2019 (COVID-19) patients are affected by influenza- and COVID-19-associated pulmonary aspergillosis (IAPA and CAPA) respectively. These viral-fungal coinfections are difficult to diagnose and are associated with increased mortality. Mechanistic insights into the development of IAPA and CAPA are a prerequisite for the development of new biomarkers and novel immunomodulatory therapeutic targets. However, data on the pathophysiology are scarce. With this study, we aimed at expanding our knowledge of IAPA and CAPA pathophysiology in an explorative way, resorting to lower respiratory tract samples and focusing on the epithelial and myeloid innate immunity components of the antifungal host response. Methods We performed nCounter gene expression analyses of 755 genes linked to innate immunity, and determined protein levels of 47 cytokines, chemokines, growth factors, and other inflammatory mediators on bronchoalveolar lavage (BAL) fluid samples from 166 ICU-admitted influenza and COVID-19-patients with or without aspergillosis. Additionally, we performed spatial transcriptomics and RNAscope on in vivo tracheobronchial biopsies from four IAPA and CAPA patients. Results Several genes encoding proteins with important effector functions in antifungal immunity are downregulated in BAL fluid of IAPA and CAPA patients compared with influenza-only or COVID-19-only patients. Cellular deconvolution of the gene expression data reveals a significantly lower BAL neutrophil fraction in CAPA patients compared to COVID-19-only patients. IAPA and CAPA patients have high BAL fluid levels of pro-inflammatory cytokines, but these are not significantly different from the levels seen in influenza-only and COVID-19-only patients. By integrating the BAL fluid cytokine levels with their respective transcriptional responses, we show that IAPA patients, and to a lesser extent CAPA patients, have an aberrant transcriptional response to pro-inflammatory cytokines as well as type I and type II interferons, which may result in poor cellular effector functions (Fig. 1a). Interferon-gamma signaling is abrogated in both IAPA and CAPA patients when compared with influenza-only and COVID-19-only patients. We observe significantly higher levels of growth factors associated with lung fibrosis in both IAPA and CAPA BAL fluid, which may contribute to the higher mortality seen in these coinfections (Fig. 1b). Using spatial transcriptomics, we show that different epithelial defense mechanisms are at play in IAPA and CAPA (Fig. 2a). Finally, using RNAscope ultrasensitive single-molecule RNA in situ hybridization, we visualize fungal and viral co-localization in CAPA tracheobronchial tissue, proving that virus-induced epithelial barrier disruption paves the way for tissue-invasive aspergillosis (Fig. 2b). Conclusion Using state-of-the-art techniques in lower respiratory tract samples obtained from a large representative patient cohort, we provide arguments for a three-level breach in antifungal immunity in IAPA and CAPA. A hampered ability to phagocytize and kill fungal spores enables Aspergillus germination and growth, leading to hyphae that are not contained because of restrained extracellular defense mechanisms. These hyphae may easily become tissue-invasive through an epithelium that is weakened by the viral infection, causing detrimental damage to the respiratory system. Functional studies will be necessary to further unravel the pathophysiology of IAPA and CAPA.

In this case report we describe a 38-year old female patient admitted to the emergency department with acute abdomen and sepsis. Broad-spectrum antibiotics were started. Abdominal imaging was inconclusive, exploratory laparoscopy showed four-quadrant peritonitis. No provoking factor could be withheld. Due to clinical deterioration the patient was transferred to the intensive care unit. Blood cultures showed the presence of group A streptococcus, and clindamycin was associated. She recovered, and could be discharged after several days. Peritonitis caused by group A

ispartof: Intensive Care Medicine vol:47 issue:9 pages:1037-1040 ispartof: location:United States status: published

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. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06431-0.

Patients with heterotaxy syndrome (HS) can present with an associated complete dorsal pancreas agenesis (DPA). They are considered to be at increased risk for developing diabetes due to a reduced functional beta cell mass (FBM) as well as for chronic pancreatitis leading to unmanageable pain. We report the case of a young woman with chronic pancreatitis due to HS and associated DPA. She presented with a severe persisting upper abdominal pain refractory to nonsurgical treatment. Unlike in previously reported cases, she had a high FBM (ie, 150% of normoglycemic controls) as determined by hyperglycemic clamp. She underwent a total pancreatectomy followed within 24 hours by an intraportal autologous islet cell transplant containing 4 × 106 beta cells (4700 islet equivalent)/kg body weight. After surgery, the pain resolved, eliminating the need for analgesics. The intraportal implant established an adequate FBM (72% of controls at posttransplant month 2), achieving glycemic control without need for insulin administration. A hyperglycemic clamp can assess the utility and efficacy of an intraportal islet cell autotransplant following total pancreatectomy in patients with HS and complete DPA.

Liposomal amphotericin B (L-AmB) is a broad-spectrum antifungal drug. Little is known about its pharmacokinetics (PK) in critically ill patients. The aim of this study was to document the PK of L-AmB in this population. It was also explored if covariates may be identified that influence its exposure. All adult, critically ill patients (at the intensive care unit or hematology ward) treated with L-AmB between October 2016 and January 2020 were eligible for this study. The administered dose was left at the discretion of the treating clinician. Plasma samples were collected at predose and 1, 2, 4, 8, 12, 16, 20 and 24 h postdose at an early (day 2-3) and/or later (≥ day 6) treatment day. Additionally, daily trough concentrations were collected until day 14. Of 33 included patients, 31 were evaluable; their median [IQR] age and body weight was 59 [54-64] years and 68 [59-77] kg, respectively. L-AmB was administered at doses between 2.7 mg/kg and 12.3 mg/kg, with a median [IQR] trough concentration of 3.1 [2.0-4.7] mg/l. The overall median area under the 24 h concentration-time curve (AUC0-24) and peak plasma concentration (Cmax) were 169.0 [117.0-253.0] mg h/l and 23.2 [16.9-33.7] mg/l, respectively. A considerable intra- and interpatient PK variability for Cmax and AUC0-24 was observed but no explaining variables, except the administered dose, could be identified. The PK of L-AmB in critically ill patients was documented. A considerable variability in exposure was observed between and within patients; however, it was not associated with a multitude of patient-related characteristics.L-AmB is marketed for decades to treat invasive fungal infections; however, not much is known about its exposure. We documented L-AmB exposure in 31 critically ill patients. Although median exposure was similar compared to noncritically ill patients, a considerable variability was observed.

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Rapid pathogen identification (ID) and antimicrobial susceptibility testing (AST) of bacteria-causing bloodstream infections can improve patients' outcome. In this study, we evaluated the performance of Alfred60AST (Alifax) which provides AST directly on positive blood culture (BC) bottles by light scattering. In a selected group of patients with a clinical suspicion of severe sepsis or at risk for infections with multiresistant organisms, we compared Alfred60AST AST results with traditional AST results (Vitek2 (bioMérieux) or disk diffusion). Discrepancy analysis was performed by Etest (bioMérieux) or broth microdilution. In total, 222 samples were evaluated. On 595 susceptibility determinations, 93.4% showed categorical agreement (CA) with the standard method. Eighty-one percent of isolates showed a 100% categorical agreement (CA) which increased to 84.3% after discrepancy analysis. There were 8 very major discrepancies (VMD), 18 major discrepancies (MD), and 13 minor discrepancies (MiD). Most discrepant results were observed for piperacillin-tazobactam (15.6%) and clindamycin (18.9%). Analysis time was 6-6.5 h for a complete Alfred60AST AST result. In addition, we evaluated the behavior of clinicians in adjusting antibiotic therapy according to the routine AST results. In 37% of all patients, antibiotic therapy was altered after reporting of AST result and adjustment was more frequent for Gram-negative than for Gram-positive isolates. With some improvements, Alfred60AST provides accurate and rapid preliminary AST results for organisms causing bloodstream infections and may have at least a potential clinical benefit in about one-third of patients with severe sepsis, by delivering faster results compared with conventional methods. ispartof: EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES vol:39 issue:1 pages:53-63 ispartof: location:Germany status: published

Objectives PTA of protein-unbound ceftriaxone may be compromised in critically ill patients with community-acquired pneumonia (CAP) with augmented renal clearance (ARC). We aimed to determine an optimized ceftriaxone dosage regimen based on the probability of developing ARC on the next day (PARC,d+1; www.arcpredictor.com). Patients and methods Thirty-three patients enrolled in a prospective cohort study were admitted to the ICU with severe CAP and treated with ceftriaxone 2 g once daily. Patients contributed 259 total ceftriaxone concentrations, collected during 1 or 2 days (±7 samples/day). Unbound fractions of ceftriaxone were determined in all peak and trough samples (n = 76). Population pharmacokinetic modelling and simulation were performed using NONMEM7.4. Target attainment was defined as an unbound ceftriaxone concentration >4 mg/L throughout the dosing interval. Results A two-compartment population pharmacokinetic model described the data well. The maximal protein-bound ceftriaxone concentration decreased with lower serum albumin. Ceftriaxone clearance increased with body weight and PARC,d+1 determined on the previous day. A high PARC,d+1 was identified as a clinically relevant predictor for underexposure on the next day (area under the receiver operating characteristics curve 0.77). Body weight had a weak predictive value and was therefore considered clinically irrelevant. Serum albumin had no predictive value. An optimal PARC,d+1 threshold of 5.7% was identified (sensitivity 73%, specificity 69%). Stratified once- or twice-daily 2 g dosing when below or above the 5.7% PARC,d+1 cut-off, respectively, was predicted to result in 81% PTA compared with 47% PTA under population-level once-daily 2 g dosing. Conclusions Critically ill patients with CAP with a high PARC,d+1 may benefit from twice-daily 2 g ceftriaxone dosing for achieving adequate exposure on the next day.

Matthias Gijsen,1,2 Omar Elkayal,1 Pieter Annaert,1,3 Ruth Van Daele,1,2 Philippe Meersseman,4 Yves Debaveye,4 Joost Wauters,4 Erwin Dreesen,1 Isabel Spriet1,2 1Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; 2Pharmacy Department, University Hospitals Leuven, Leuven, Belgium; 3BioNotus, Niel, Belgium; 4Department of Cellular and Molecular Medicine, KU Leuven, Leuven, BelgiumCorrespondence: Matthias GijsenPharmacy Department, University Hospitals Leuven, Herestraat 49, Leuven, 3000, BelgiumTel +32 16 340087Fax +32 16 343080Email mathias.gijsen@uzleuven.bePurpose: Critically ill patients with preserved or increased renal function have been shown to be at risk of underexposure to meropenem. Although many meropenem population pharmacokinetic (PK) models have been published, there is no large prospective population PK study with rich sampling focusing on patients most at risk of suboptimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Therefore, the aim of the present study was to evaluate PK/PD target attainment and to perform a thorough covariate screening using population PK modelling of meropenem in septic patients with preserved or increased renal function.Patients and Methods: A single-centre prospective observational PK study was performed in the intensive care unit (ICU) of the University Hospitals Leuven. Patients with severe sepsis or septic shock and treated with meropenem in the ICU were screened for inclusion. Patients were excluded if they received renal replacement therapy or had an estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology collaboration equation < 70 mL/min/1.73m2 on the day of PK sampling. Successful PK/PD target attainment was defined as an unbound meropenem trough concentration above 2 mg/L or 8 mg/L. Population PK modelling was performed with NONMEM7.4.Results: In total, 58 patients were included, contributing 345 plasma samples over 70 dosing intervals. The 2 mg/L and 8 mg/L targets were successfully attained in 46% and 11% of all dosing intervals, respectively. A two-compartment population PK model with linear elimination and interindividual variability on clearance best described meropenem PK. The estimated creatinine clearance according to the Cockcroft-Gault equation was the only covariate retained during population PK analysis.Conclusion: This study provided detailed insight into meropenem PK in critically ill patients with preserved or increased renal function. We observed poor PK/PD target attainment, for which renal function was the only significant covariate.Trial Registration: This study is registered at ClinicalTrials.gov (NCT03560557).Keywords: intensive care, PK/PD, exposure, dose optimization, augmented renal clearance

Critically ill patients are thought to develop maladaptive glucocorticoid-resistance which convinces many clinicians to administer stress doses of glucocorticoids to overcome this state of glucocorticoid-resistance. However, supportive data arises mainly from whole blood cells. It is currently not known if the observed changes in regulators and markers of glucocorticoid signaling and activity are also present in other cell and tissue types with a role in critical illness. We quantified regulators and markers of glucocorticoid signaling and activity in several cell and tissue types in critically ill humans and animals and in healthy controls. We found that throughout critical illness, glucocorticoid activity appeared suppressed in neutrophils, but upregulated in monocytes and skeletal muscle. Also in vital tissues GRα-signaling was altered in a tissue-specific, largely time-independent manner. Increasing systemic glucocorticoid availability increased glucocorticoid activity in adipose tissue, diaphragm and lung, whereas in immune cells and other tissues regulatory pathways counteracted. These data argue against glucocorticoid-treatable generalized glucocorticoid resistance and rather point towards an adaptive response in each specific cell or tissue type to optimally guide the beneficial actions of glucocorticoids to the tissues that need it while protecting collateral undesirable effects in tissue that are harmed by elevated systemic glucocorticoid availability. Presentation: Monday, June 13, 2022 11:45 a.m. - 12:00 p.m.

BACKGROUND Isavuconazole is a triazole antifungal drug, approved for the treatment of invasive aspergillosis and mucormycosis. It has been previously reported that an interaction between flucloxacillin and voriconazole may lead to subtherapeutic voriconazole exposure, when used concomitantly. Since isavuconazole is also metabolised via cytochrome P450 enzymes, the same interaction may be expected. OBJECTIVES We aim to document exposure to isavuconazole in patients concomitantly treated with flucloxacillin. PATIENTS We report two patients treated with both isavuconazole and flucloxacillin, in whom we determined isavuconazole concentrations. RESULTS Low isavuconazole trough concentrations (

Objectives: Coronavirus disease 2019 (COVID-19) -associated pulmonary aspergillosis (CAPA) has emerged as a complication in critically ill COVID-19 patients. The objectives of this multinational study were to determine the prevalence of CAPA in patients with COVID-19 in intensive care units (ICU) and to investigate risk factors for CAPA as well as outcome. Methods: The European Confederation of Medical Mycology (ECMM) conducted a multinational study including 20 centres from nine countries to assess epidemiology, risk factors and outcome of CAPA. CAPA was defined according to the 2020 ECMM/ISHAM consensus definitions. Results: A total of 592 patients were included in this study, including 11 (1.9%) patients with histologically proven CAPA, 80 (13.5%) with probable CAPA, 18 (3%) with possible CAPA and 483 (81.6%) without CAPA. CAPA was diagnosed a median of 8 days (range 0–31 days) after ICU admission predominantly in older patients (adjusted hazard ratio (aHR) 1.04 per year; 95% CI 1.02–1.06) with any form of invasive respiratory support (HR 3.4; 95% CI 1.84–6.25) and receiving tocilizumab (HR 2.45; 95% CI 1.41–4.25). Median prevalence of CAPA per centre was 10.7% (range 1.7%–26.8%). CAPA was associated with significantly lower 90-day ICU survival rate (29% in patients with CAPA versus 57% in patients without CAPA; Mantel–Byar p < 0.001) and remained an independent negative prognostic variable after adjusting for other predictors of survival (HR 2.14; 95% CI 1.59–2.87, p ≤ 0.001). Conclusion: Prevalence of CAPA varied between centres. CAPA was significantly more prevalent among older patients, patients receiving invasive ventilation and patients receiving tocilizumab, and was an independent strong predictor of ICU mortality.

In times where only a few novel antibiotics are to be expected, antimicrobial resistance remains an expanding global health threat. In case of chronic infections caused by therapy-resistant pathogens, physicians have limited therapeutic options, which are often associated with detrimental consequences for the patient. This has resulted in a renewed interest in alternative strategies, such as bacteriophage (phage) therapy. However, there are still important hurdles that currently impede the more widespread implementation of phage therapy in clinical practice. First, the limited number of good-quality case series and clinical trials have failed to show the optimal application protocol in terms of route of administration, frequency of administration, treatment duration and phage titer. Second, there is limited information on the systemic effects of phage therapy. Finally, in the past, phage therapy has been applied intuitively in terms of the selection of phages and their combination as parts of phage cocktails. This has led to an enormous heterogeneity in previously published studies, resulting in a lack of reliable safety and efficacy data for phage therapy. We hereby present a study protocol that addresses these scientific hurdles using a multidisciplinary approach, bringing together the experience of clinical, pharmaceutical and molecular microbiology experts. ispartof: VIRUSES-BASEL vol:13 issue:8 ispartof: location:Switzerland status: published

Background: Voriconazole is one of the first-line therapies for invasive pulmonary aspergillosis. Drug concentrations might be significantly influenced by the use of extracorporeal membrane oxygenation (ECMO). We aimed to assess the effect of ECMO on voriconazole exposure in a large patient population. Methods: Critically ill patients from eight centers in four countries treated with voriconazole during ECMO support were included in this retrospective study. Voriconazole concentrations were collected in a period on ECMO and before/after ECMO treatment. Multivariate analyses were performed to evaluate the effect of ECMO on voriconazole exposure and to assess the impact of possible saturation of the circuit’s binding sites over time. Results: Sixty-nine patients and 337 samples (190 during and 147 before/after ECMO) were analyzed. Subtherapeutic concentrations (&lt, 2 mg/L) were observed in 56% of the samples during ECMO and 39% without ECMO (p = 0.80). The median trough concentration, for a similar daily dose, was 2.4 (1.2–4.7) mg/L under ECMO and 2.5 (1.4–3.9) mg/L without ECMO (p = 0.58). Extensive inter-and intrasubject variability were observed. Neither ECMO nor squared day of ECMO (saturation) were retained as significant covariates on voriconazole exposure. Conclusions: No significant ECMO-effect was observed on voriconazole exposure. A large proportion of patients had voriconazole subtherapeutic concentrations.

The empiric antibiotic regimen started after deep cultures and explantation of the graft mostly do not cover antifungals. We retrospectively studied the outcome of candida compared to non-candida VGI and assessed whether these results could justify the addition of antifungals to the empiric antibiotics in the early postoperative period.All patients treated for infected aorto(ilio)femoral graft with excision and reconstruction at the vascular department of University Hospitals Leuven between January 2010 and 2017 (n = 56) were studied retrospectively. Patients were allocated to the candida group (n = 10) or non-candida group (n = 46) according to the presence of Candida in deep culture isolates.All-cause mortality was significantly higher in the candida group compared to the non-candida group. All-cause 30-day mortality was 40% and 13% for both groups respectively (P = 0.066). At 5 years this was 90% and 46% respectively (P = 0.014). In the candida group 6 patients (60%) had to be revised in the operating room due to bleeding, compared to 5 patients (11%) in the non-candida group (P = 0.002). Two patients (20%) and 5 patients (11%) had to be readmitted to the ICU, respectively.Survival of candida related VGI is significantly worse, especially in the first 5 postoperative months. This could justify the addition of an antifungal to the early empiric postoperative antibiotic cocktail, especially in patients with an aorto-enteric fistula. A cost-benefit analysis could be useful to evaluate the yield.

Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected., Postmortem samples of respiratory and olfactory mucosa and whole olfactory bulbs are harvested immediately after the death of COVID-19 patients revealing ciliated cells and sustentacular cells but not olfactory sensory neurons as the main target cell types for SARS-CoV-2 infection and replication.

Existing evidence is inconclusive whether meropenem dosing should be adjusted in patients receiving extracorporeal membrane oxygenation (ECMO). Therefore, the aim of this observational matched cohort study was to evaluate the effect of ECMO on pharmacokinetic (PK) variability and target attainment (TA) of meropenem. Patients admitted to the intensive care unit (ICU) simultaneously treated with meropenem and ECMO were eligible. Patients were matched 1:1, based on renal function and body weight, with non-ECMO ICU patients. Meropenem blood sampling was performed over one or two dosing intervals. Population PK modelling was performed using NONMEM7.5. TA was defined as free meropenem concentrations &gt, 2 or 8 mg/L (i.e., 1 or 4× minimal inhibitory concentration, respectively) throughout the whole dosing interval. In total, 25 patients were included, contributing 27 dosing intervals. The overall TA was 56% and 26% for the 2 mg/L and 8 mg/L target, respectively. Population PK modelling identified estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology equation and body weight, but not ECMO, as significant predictors. In conclusion, TA of meropenem was confirmed to be poor under standard dosing in critically ill patients but was not found to be influenced by ECMO. Future studies should focus on applying dose optimisation strategies for meropenem based on renal function, regardless of ECMO.

We read with great interest the paper entitled 'Optimization of fluconazole dosing for the prevention and treatment of invasive candidiasis based on the pharmacokinetics of fluconazole in critically ill patients' recently published by Boonstra JM and colleagues (1).….