Monitoring circulating dipeptidyl peptidase 3 (DPP3) predicts improvement of organ failure and survival in sepsis: a prospective observational multinational study.

BACKGROUND: Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in the degradation of various cardiovascular and endorphin mediators. High levels of circulating DPP3 (cDPP3) indicate a high risk of organ dysfunction and mortality in cardiogenic shock patients. METHODS: The aim was to assess relationships between cDPP3 during the initial intensive care unit (ICU) stay and short-term outcome in the AdrenOSS-1, a prospective observational multinational study in twenty-four ICU centers in five countries. AdrenOSS-1 included 585 patients admitted to the ICU with severe sepsis or septic shock. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by the Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use and need for renal replacement therapy. cDPP3 levels were measured upon admission and 24 h later. RESULTS: Median [IQR] cDPP3 concentration upon admission was 26.5 [16.2-40.4] ng/mL. Initial SOFA score was 7 [5-10], and 28-day mortality was 22%. We found marked associations between cDPP3 upon ICU admission and 28-day mortality (unadjusted standardized HR 1.8 [CI 1.6-2.1]; adjusted HR 1.5 [CI 1.3-1.8]) and between cDPP3 levels and change in renal and liver SOFA score (p = 0.0077 and 0.0009, respectively). The higher the initial cDPP3 was, the greater the need for organ support and vasopressors upon admission; the longer the need for vasopressor(s), mechanical ventilation or RRT and the higher the need for fluid load (all p < 0.005). In patients with cDPP3 > 40.4 ng/mL upon admission, a decrease in cDPP3 below 40.4 ng/mL after 24 h was associated with an improvement of organ function at 48 h and better 28-day outcome. By contrast, persistently elevated cDPP3 at 24 h was associated with worsening organ function and high 28-day mortality. CONCLUSIONS: Admission levels and rapid changes in cDPP3 predict outcome during sepsis. Trial Registration ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015.

Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial.

IMPORTANCE: Norepinephrine, the first-line vasopressor for septic shock, is not always effective and has important catecholaminergic adverse effects. Selepressin, a selective vasopressin V1a receptor agonist, is a noncatecholaminergic vasopressor that may mitigate sepsis-induced vasodilatation, vascular leakage, and edema, with fewer adverse effects. OBJECTIVE: To test whether selepressin improves outcome in septic shock. DESIGN, SETTING, AND PARTICIPANTS: An adaptive phase 2b/3 randomized clinical trial comprising 2 parts that included adult patients (n = 868) with septic shock requiring more than 5 µg/min of norepinephrine. Part 1 used a Bayesian algorithm to adjust randomization probabilities to alternative selepressin dosing regimens and to trigger transition to part 2, which would compare the best-performing regimen with placebo. The trial was conducted between July 2015 and August 2017 in 63 hospitals in Belgium, Denmark, France, the Netherlands, and the United States, and follow-up was completed by May 2018. INTERVENTIONS: Random assignment to 1 of 3 dosing regimens of selepressin (starting infusion rates of 1.7, 2.5, and 3.5 ng/kg/min; n = 585) or to placebo (n = 283), all administered as continuous infusions titrated according to hemodynamic parameters. MAIN OUTCOMES AND MEASURES: Primary end point was ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) of commencing study drug. Key secondary end points were 90-day mortality, kidney replacement therapy-free days, and ICU-free days. RESULTS: Among 868 randomized patients, 828 received study drug (mean age, 66.3 years; 341 [41.2%] women) and comprised the primary analysis cohort, of whom 562 received 1 of 3 selepressin regimens, 266 received placebo, and 817 (98.7%) completed the trial. The trial was stopped for futility at the end of part 1. Median study drug duration was 37.8 hours (IQR, 17.8-72.4). There were no significant differences in the primary end point (ventilator- and vasopressor-free days: 15.0 vs 14.5 in the selepressin and placebo groups; difference, 0.6 [95% CI, -1.3 to 2.4]; P = .30) or key secondary end points (90-day mortality, 40.6% vs 39.4%; difference, 1.1% [95% CI, -6.5% to 8.8%]; P = .77; kidney replacement therapy-free days: 18.5 vs 18.2; difference, 0.3 [95% CI, -2.1 to 2.6]; P = .85; ICU-free days: 12.6 vs 12.2; difference, 0.5 [95% CI, -1.2 to 2.2]; P = .41). Adverse event rates included cardiac arrhythmias (27.9% vs 25.2% of patients), cardiac ischemia (6.6% vs 5.6%), mesenteric ischemia (3.2% vs 2.6%), and peripheral ischemia (2.3% vs 2.3%). CONCLUSIONS AND RELEVANCE: Among patients with septic shock receiving norepinephrine, administration of selepressin, compared with placebo, did not result in improvement in vasopressor- and ventilator-free days within 30 days. Further research would be needed to evaluate the potential role of selepressin for other patient-centered outcomes in septic shock. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02508649.

Thoracic Epidural Analgesia and Mortality in Acute Pancreatitis: A Multicenter Propensity Analysis.

OBJECTIVE: Recent preclinical and clinical data suggest that thoracic epidural analgesia, a technique primarily aimed at decreasing pain, might exert anti-inflammatory effects, enhance splanchnic and pancreatic blood flow during acute pancreatitis; however, the influence of epidural analgesia on mortality remains under investigated in this setting. This study was therefore designed to assess the impact of epidural analgesia on mortality in ICU patients with acute pancreatitis. DESIGN: Multicenter retrospective, observational, cohort study. SETTING: Seventeen French and Belgian ICUs. PATIENTS: All patients admitted to with acute pancreatitis between June 2009 and March 2014. INTERVENTIONS: The primary exposure was thoracic epidural analgesia versus standard care without epidural analgesia. The primary outcome was 30-day mortality. Propensity analyses were used to control for bias in treatment assignment and prognostic imbalances. MEASUREMENTS AND MAIN RESULTS: One thousand three ICU patients with acute pancreatitis were enrolled, of whom 212 died within 30 days. Epidural analgesia was used in 46 patients and was associated with reduced mortality in unadjusted analyses (4% vs. 22%; p = 0.003). After adjustment for baseline variables associated with mortality, epidural analgesia was still an independent predictor of 30-day mortality (adjusted odds ratio, 0.10; [95% CI, 0.02-0.49]; p = 0.004). Using propensity score analysis, the risk of all-cause 30-day mortality in patients with acute pancreatitis receiving epidural analgesia was significantly lower than that in matched patients who did not receive epidural analgesia (2% vs. 17%; p = 0.01). CONCLUSIONS: Among critically ill patients with acute pancreatitis, mortality at 30 days was lower in patients who received epidural analgesia than in comparable patients who did not. These findings support ongoing research on the use of epidural analgesia as a therapeutic intervention in acute pancreatitis.

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study.

BACKGROUND: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. METHODS: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. RESULTS: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). CONCLUSIONS: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02393781 . Registered on March 19, 2015.

Decontamination Strategies and Bloodstream Infections With Antibiotic-Resistant Microorganisms in Ventilated Patients: A Randomized Clinical Trial.

Importance: The effects of chlorhexidine (CHX) mouthwash, selective oropharyngeal decontamination (SOD), and selective digestive tract decontamination (SDD) on patient outcomes in ICUs with moderate to high levels of antibiotic resistance are unknown. Objective: To determine associations between CHX 2%, SOD, and SDD and the occurrence of ICU-acquired bloodstream infections with multidrug-resistant gram-negative bacteria (MDRGNB) and 28-day mortality in ICUs with moderate to high levels of antibiotic resistance. Design, Setting, and Participants: Randomized trial conducted from December 1, 2013, to May 31, 2017, in 13 European ICUs where at least 5% of bloodstream infections are caused by extended-spectrum ß-lactamase-producing Enterobacteriaceae. Patients with anticipated mechanical ventilation of more than 24 hours were eligible. The final date of follow-up was September 20, 2017. Interventions: Standard care was daily CHX 2% body washings and a hand hygiene improvement program. Following a baseline period from 6 to 14 months, each ICU was assigned in random order to 3 separate 6-month intervention periods with either CHX 2% mouthwash, SOD (mouthpaste with colistin, tobramycin, and nystatin), or SDD (the same mouthpaste and gastrointestinal suspension with the same antibiotics), all applied 4 times daily. Main Outcomes and Measures: The occurrence of ICU-acquired bloodstream infection with MDRGNB (primary outcome) and 28-day mortality (secondary outcome) during each intervention period compared with the baseline period. Results: A total of 8665 patients (median age, 64.1 years; 5561 men [64.2%]) were included in the study (2251, 2108, 2224, and 2082 in the baseline, CHX, SOD, and SDD periods, respectively). ICU-acquired bloodstream infection with MDRGNB occurred among 144 patients (154 episodes) in 2.1%, 1.8%, 1.5%, and 1.2% of included patients during the baseline, CHX, SOD, and SDD periods, respectively. Absolute risk reductions were 0.3% (95% CI, -0.6% to 1.1%), 0.6% (95% CI, -0.2% to 1.4%), and 0.8% (95% CI, 0.1% to 1.6%) for CHX, SOD, and SDD, respectively, compared with baseline. Adjusted hazard ratios were 1.13 (95% CI, 0.68-1.88), 0.89 (95% CI, 0.55-1.45), and 0.70 (95% CI, 0.43-1.14) during the CHX, SOD, and SDD periods, respectively, vs baseline. Crude mortality risks on day 28 were 31.9%, 32.9%, 32.4%, and 34.1% during the baseline, CHX, SOD, and SDD periods, respectively. Adjusted odds ratios for 28-day mortality were 1.07 (95% CI, 0.86-1.32), 1.05 (95% CI, 0.85-1.29), and 1.03 (95% CI, 0.80-1.32) for CHX, SOD, and SDD, respectively, vs baseline. Conclusions and Relevance: Among patients receiving mechanical ventilation in ICUs with moderate to high antibiotic resistance prevalence, use of CHX mouthwash, SOD, or SDD was not associated with reductions in ICU-acquired bloodstream infections caused by MDRGNB compared with standard care. Trial Registration: ClinicalTrials.gov Identifier: NCT02208154.

Aerosol delivery during invasive mechanical ventilation: a systematic review.

BACKGROUND: This systematic review aimed to assess inhaled drug delivery in mechanically ventilated patients or in animal models. Whole lung and regional deposition and the impact of the ventilator circuit, the artificial airways and the administration technique for aerosol delivery were analyzed. METHODS: In vivo studies assessing lung deposition during invasive mechanical ventilation were selected based on a systematic search among four databases. Two investigators independently assessed the eligibility and the risk of bias. RESULTS: Twenty-six clinical and ten experimental studies were included. Between 30% and 43% of nominal drug dose was lost to the circuit in ventilated patients. Whole lung deposition of up to 16% and 38% of nominal dose (proportion of drug charged in the device) were reported with nebulizers and metered-dose inhalers, respectively. A penetration index inferior to 1 observed in scintigraphic studies indicated major proximal deposition. However, substantial concentrations of antibiotics were measured in the epithelial lining fluid (887 (406-12,819) µg/mL of amikacin) of infected patients and in sub-pleural specimens (e.g., 197 µg/g of amikacin) dissected from infected piglets, suggesting a significant distal deposition. The administration technique varied among studies and may explain a degree of the variability of deposition that was observed. CONCLUSIONS: Lung deposition was lower than 20% of nominal dose delivered with nebulizers and mostly occurred in proximal airways. Further studies are needed to link substantial concentrations of antibiotics in infected pulmonary fluids to pulmonary deposition. The administration technique with nebulizers should be improved in ventilated patients in order to ensure an efficient but safe, feasible and reproducible technique.

A randomized placebo-controlled phase II study of a Pseudomonas vaccine in ventilated ICU patients.

BACKGROUND: Currently, no vaccine against Pseudomonas is available. IC43 is a new, recombinant, protein (OprF/I)-based vaccine against the opportunistic pathogen, Pseudomonas aeruginosa, a major cause of serious hospital-acquired infections. IC43 has proven immunogenicity and tolerability in healthy volunteers, patients with burns, and patients with chronic lung diseases. In order to assess the immunogenicity and safety of IC43 in patients who are most at risk of acquiring Pseudomonas infections, it was evaluated in mechanically ventilated ICU patients. METHODS: We conducted a randomized, placebo-controlled, partially blinded study in mechanically ventilated ICU patients. The immunogenicity of IC43 at day 14 was determined as the primary endpoint, and safety, efficacy against P. aeruginosa infections, and all-cause mortality were evaluated as secondary endpoints. Vaccinations (100 µg or 200 µg IC43 with adjuvant, or 100 µg IC43 without adjuvant, or placebo) were given twice in a 7-day interval and patients were followed up for 90 days. RESULTS: Higher OprF/I IgG antibody titers were seen at day 14 for all IC43 groups versus placebo (P < 0.0001). Seroconversion (≥4-fold increase in OprF/I IgG titer from days 0 to 14) was highest with 100 µg IC43 without adjuvant (80.6%). There were no significant differences in P. aeruginosa infection rates, with a low rate of invasive infections (pneumonia or bacteremia) in the IC43 groups (11.2-14.0%). Serious adverse events (SAEs) considered possibly related to therapy were reported by 2 patients (1.9%) in the group of 100 µg IC43 with adjuvant. Both SAEs resolved and no deaths were related to study treatment. Local tolerability symptoms were mild and rare (<5% of patients), a low rate of treatment-related treatment-emergent adverse events (3.1-10.6%) was observed in the IC43 groups. CONCLUSION: This phase II study has shown that IC43 vaccination of ventilated ICU patients produced a significant immunogenic effect. P. aeruginosa infection rates did not differ significantly between groups. In the absence of any difference in immune response following administration of 100 µg IC43 without adjuvant compared with 200 µg IC43 with adjuvant, the 100 µg dose without adjuvant was considered for further testing of its possible benefit of improved outcomes. There were no safety or mortality concerns. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00876252 . Registered on 3 April 2009.

Temocillin (6 g daily) in critically ill patients: continuous infusion versus three times daily administration.

OBJECTIVES: The growing incidence of infections caused by Enterobacteriaceae producing ESBLs has led to increased use of carbapenems. Temocillin, which resists most ß-lactamases, may be a useful alternative. The aim of this study was to assess the pharmacokinetics and target attainment rates of 6 g of temocillin daily divided into three administrations every 8 h (three times daily) or administered by continuous infusion in critically ill patients. PATIENTS AND METHODS: This was a prospective, two-centre, randomized, controlled study in patients with intra-abdominal or lower respiratory tract infections caused by Enterobacteriaceae. RESULTS: Thirty-two patients were included and analysed for clinical efficacy, and pharmacokinetics were measured in 29 of them. Four patients undergoing continuous veno-venous haemofiltration (CVVH) were analysed separately. Mean, median and range of percentages of the dosing interval during which the free drug concentration remained >16 mg/L were 76.4, 98 and 18.7-98.9 in patients treated three times daily and 98.9, 89.7 and 36.4-99.9 in patients with continuous infusion, respectively. Clinical cure rates were 79% and 93% in each of these groups, respectively (not significant). Patients with CVVH received a daily dose of 750 mg given by continuous infusion and had a mean free drug concentration of only 13.8 ±â€Š1.9 mg/L. No adverse event attributable to temocillin was observed. CONCLUSIONS: Temocillin (6 g daily) given by continuous infusion allows a larger proportion of critically ill patients to have free drug serum concentrations covering infections caused by Enterobacteriaceae with an MIC of 16 mg/L compared with administration three times daily. Clinical efficacy compared with carbapenems in documented severe infections needs to be further studied.

Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.

IMPORTANCE: Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. OBJECTIVE: To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. INTERVENTIONS: Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively. MAIN OUTCOME MEASURES: The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. RESULTS: Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, -1.1; 95% CI, -5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. CONCLUSIONS AND RELEVANCE: Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00334828.

Case Report: Late Reactivation of Herpes B Virus After a Monkey Bite: A Case of Severe Meningoencephalitis.

Macacine alphaherpesvirus 1, also known as herpes B virus (BV), is an alphaherpesvirus endemic to several macaque species, capable of causing zoonotic infections in humans, with high mortality rates. Evidence of reactivation in humans has rarely been reported. Here we depict a case of BV reactivation after 54 years, leading to severe meningoencephalitis. This case supports the use of antiviral prophylaxis in patients surviving a confirmed BV central nervous system infection. We sequenced DNA from BV obtained from the patient's cerebrospinal fluid. Phylogenetic analysis showed significant divergence in the clustering of this particular BV strain compared with other known BVs. Therefore, additional efforts are needed to obtain a broader sequence landscape from BVs circulating in monkeys.

Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial.

RATIONALE: Severe community-acquired pneumonia (sCAP) is a leading cause of death worldwide. Adjunctive therapies for sCAP are needed to further improve outcome. A systemic inhibitor of coagulation, tifacogin (recombinant human tissue factor pathway inhibitor) seemed to provide mortality benefit in the sCAP subgroup of a previous sepsis trial. OBJECTIVES: Evaluate the impact of adjunctive tifacogin on mortality in patients with sCAP. METHODS: A multicenter, randomized, placebo-controlled, double-blind, three-arm study was conducted from July 2005 to June 2008 at 188 centers in North and South America, Europe, South Africa, Asia, Australia, and New Zealand. Adults with sCAP were randomized to receive a continuous intravenous infusion of tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, or matching placebo over 96 hours. MEASUREMENTS AND MAIN RESULTS: Severity-adjusted 28-day all-cause mortality. Of 2,138 randomized patients, 946, 238, and 918 received tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, and placebo, respectively. Tifacogin 0.075 mg/kg/h was discontinued after the first interim analysis according to prespecified futility criterion. The 28-day all-cause mortality rates were similar between the 0.025 mg/kg/h (18%) and placebo groups (17.9%) (P = 0.56). Greater reduction in prothrombin fragment 1+2 and thrombin antithrombin complexes levels relative to baseline throughout the first 96 hours was found with tifacogin 0.025 mg/kg/h than with placebo. The incidence of adverse events and serious adverse events were comparable between the tifacogin 0.025 mg/kg/h and placebo groups. CONCLUSIONS: Tifacogin showed no mortality benefit in patients with sCAP despite evidence of biologic activity.

Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial.

PURPOSE: Investigate safety and tolerability of adrecizumab, a humanized monoclonal adrenomedullin antibody, in septic shock patients with high adrenomedullin. METHODS: Phase-2a, double-blind, randomized, placebo-controlled biomarker-guided trial with a single infusion of adrecizumab (2 or 4 mg/kg b.w.) compared to placebo. Patients with adrenomedullin above 70 pg/mL, < 12 h of vasopressor start for septic shock were eligible. Randomization was 1:1:2. Primary safety (90-day mortality, treatment emergent adverse events (TEAE)) and tolerability (drug interruption, hemodynamics) endpoints were recorded. Efficacy endpoints included the Sepsis Support Index (SSI, reflecting ventilator- and shock-free days alive), change in Sequential-related Organ Failure Assessment (SOFA) and 28-day mortality. RESULTS: 301 patients were enrolled (median time of 8.5 h after vasopressor start). Adrecizumab was well tolerated (one interruption, no hemodynamic alteration) with no differences in frequency and severity in TEAEs between treatment arms (TEAE of grade 3 or higher: 70.5% in the adrecizumab group and 71.1% in the placebo group) nor in 90-day mortality. Difference in change in SSI between adrecizumab and placebo was 0.72 (CI -1.93-0.49, p = 0.24). Among various secondary endpoints, delta SOFA score (defined as maximum versus minimum SOFA) was more pronounced in the adrecizumab combined group compared to placebo [difference at 0.76 (95% CI 0.18-1.35); p = 0.007]. 28-day mortality in the adrecizumab group was 23.9% and 27.7% in placebo with a hazard ratio of 0.84 (95% confidence interval 0.53-1.31, log-rank p = 0.44). CONCLUSIONS: Overall, we successfully completed a randomized trial evaluating selecting patients for enrolment who had a disease-related biomarker. There were no overt signals of harm with using two doses of the adrenomedullin antibody adrecizumab; however, further randomized controlled trials are required to confirm efficacy and safety of this agent in septic shock patients.

Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock.

INTRODUCTION: It has been proposed that doses of amikacin of >15 mg/kg should be used in conditions associated with an increased volume of distribution (Vd), such as severe sepsis and septic shock. The primary aim of this study was to determine whether 25 mg/kg (total body weight) of amikacin is an adequate loading dose for these patients. METHODS: This was an open, prospective, multicenter study in four Belgian intensive care units (ICUs). All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom amikacin treatment was indicated, were included in the study. RESULTS: In 74 patients, serum samples were collected before (t = 0 h) and 1 hour (peak), 1 hour 30 minutes, 4 hours 30 minutes, 8 hours, and 24 hours after the first dose of amikacin. Blood amikacin levels were measured by using a validated fluorescence polarization immunoassay method, and an open two-compartment model with first-order elimination was fitted to concentrations-versus-time data for amikacin (WinNonlin). In 52 (70%) patients, peak serum concentrations were >64 microg/ml, which corresponds to 8 times the clinical minimal inhibitory concentration (MIC) breakpoints defined by EUCAST for Enterobacteriaceae and Pseudomonas aeruginosa (S<8, R>16 microg/ml). Vd was 0.41 (0.29 to 0.51) L/kg; elimination half-life, 4.6 (3.2 to 7.8) hours; and total clearance, 1.98 (1.28 to 3.54) ml/min/kg. No correlation was found between the amikacin peak and any clinical or hemodynamic variable. CONCLUSIONS: As patients with severe sepsis and septic shock have an increased Vd, a first dose of >or= 25 mg/kg (total body weight) of amikacin is required to reach therapeutic peak concentrations. However, even with this higher amikacin dose, the peak concentration remained below therapeutic target levels in about one third of these patients. Optimizing aminoglycoside therapy should be achieved by tight serum-concentration monitoring because of the wide interindividual variability of pharmacokinetic abnormalities.

Insufficient ß-lactam concentrations in the early phase of severe sepsis and septic shock.

INTRODUCTION: Altered pharmacokinetics (PK) in critically ill patients can result in insufficient serum ß-lactam concentrations when standard dosages are administered. Previous studies on ß-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock. METHODS: Open, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration. RESULTS: 80 patients were treated with piperacillin-tazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T > 4 × MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 µg/mL), 45% for ceftazidime (MIC = 32 µg/mL), 34% for cefepime (MIC = 32 µg/mL), and 33% for piperacillin-tazobactam (MIC = 64 µg/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillin-tazobactam. CONCLUSIONS: Serum concentrations of the antibiotic after the first dose were acceptable only for meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock.

What is the optimal loading dose of broad-spectrum ß-lactam antibiotics in septic patients? Results from pharmacokinetic simulation modelling.

Optimal loading doses of ß-lactams to rapidly achieve adequate drug concentrations in critically ill patients are unknown. This was a post-hoc analysis of a prospective study that evaluated broad-spectrum ß-lactams [piperacillin (PIP), ceftazidime (CAZ), cefepime (FEP) and meropenem (MEM)] pharmacokinetics (PKs) in patients with sepsis or septic shock (n = 88). Monte Carlo simulation was performed for 1000 virtual patients using specific sets of covariates for various dosing regimens and different durations of administration. Pharmacodynamic (PD) targets were considered as drug concentrations exceeding at least 50% of time above four times the minimum inhibitory concentration (T>4 × MIC) of Pseudomonas aeruginosa, according to EUCAST criteria, for PIP, 70%T>4 × MIC for CAZ and FEP and 40%T>4 × MIC for MEM. The probability of target attainment (PTA) was derived by calculating the percentage of patients who attained the PK/PD target at each MIC. The optimal loading dose was defined as the one associated with a ≥90% probability to achieve the PD targets. Our simulation model identified an optimal loading dose for PIP of 8 g given as a 3-h infusion (PTA of 96.2%), for CAZ and FEP of 4 g given as a 3-h infusion (PTA of 96.5% and 98.4%, respectively), and for MEM of 2 g given as a 30-min infusion (PTA of 93.4%), with the following antibiotic dose administered 6 h thereafter regardless of the drug. A higher first dose of broad-spectrum ß-lactams should be given to adequately treat less-susceptible pathogens in septic patients. These findings need to be validated in a prospective study.

Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial.

PURPOSE: Nangibotide is a specific TREM-1 inhibitor that tempered deleterious host-pathogens interactions, restored vascular function, and improved survival, in animal septic shock models. This study evaluated the safety and pharmacokinetics of nangibotide and its effects on clinical and pharmacodynamic parameters in septic shock patients. METHODS: This was a multicenter randomized, double-blind, two-stage study. Patients received either continuous infusion of nangibotide (0.3, 1.0, or 3.0 mg/kg/h) or placebo. Treatment began < 24 h after shock onset and continued for up to 5 days. Safety primary outcomes were adverse events (AEs), whether serious or not, and death. Exploratory endpoints evaluated nangibotide effects on pharmacodynamics, organ function, and mortality, and were analyzed according to baseline sTREM-1 concentrations. RESULTS: Forty-nine patients were randomized. All treatment emergent AEs (TEAEs) were collected until Day 28. No significant differences were observed in TEAEs between treatment groups. No drug withdrawal linked to TEAE nor appearance of anti-drug antibodies were reported. Nangibotide pharmacokinetics appeared to be dose-proportional and clearance was dose-independent. Nangibotide did not significantly affect pharmacodynamic markers. Decrease in SOFA score LS mean change (± SE) from baseline to Day 5 in pooled nangibotide groups versus placebo was - 0.7 (± 0.85) in the randomized population and - 1.5 (± 1.12) in patients with high baseline plasma sTREM-1 concentrations (non-significant). This pattern was similar to organ support end points. CONCLUSION: No significant increases in TEAEs were detected in nangibotide-treated patients versus placebo. These results encourage further evaluation of nangibotide and further exploration of plasma sTREM-1 concentrations as a predictive efficacy biomarker.

Impact of solid cancer on in-hospital mortality overall and among different subgroups of patients with COVID-19: a nationwide, population-based analysis.

BACKGROUND: Cancer seems to have an independent adverse prognostic effect on COVID-19-related mortality, but uncertainty exists regarding its effect across different patient subgroups. We report a population-based analysis of patients hospitalised with COVID-19 with prior or current solid cancer versus those without cancer. METHODS: We analysed data of adult patients registered until 24 May 2020 in the Belgian nationwide database of Sciensano. The primary objective was in-hospital mortality within 30 days of COVID-19 diagnosis among patients with solid cancer versus patients without cancer. Severe event occurrence, a composite of intensive care unit admission, invasive ventilation and/or death, was a secondary objective. These endpoints were analysed across different patient subgroups. Multivariable logistic regression models were used to analyse the association between cancer and clinical characteristics (baseline analysis) and the effect of cancer on in-hospital mortality and on severe event occurrence, adjusting for clinical characteristics (in-hospital analysis). RESULTS: A total of 13 594 patients (of whom 1187 with solid cancer (8.7%)) were evaluable for the baseline analysis and 10 486 (892 with solid cancer (8.5%)) for the in-hospital analysis. Patients with cancer were older and presented with less symptoms/signs and lung imaging alterations. The 30-day in-hospital mortality was higher in patients with solid cancer compared with patients without cancer (31.7% vs 20.0%, respectively; adjusted OR (aOR) 1.34; 95% CI 1.13 to 1.58). The aOR was 3.84 (95% CI 1.94 to 7.59) among younger patients (<60 years) and 2.27 (95% CI 1.41 to 3.64) among patients without other comorbidities. Severe event occurrence was similar in both groups (36.7% vs 28.8%; aOR 1.10; 95% CI 0.95 to 1.29). CONCLUSIONS: This population-based analysis demonstrates that solid cancer is an independent adverse prognostic factor for in-hospital mortality among patients with COVID-19. This adverse effect was more pronounced among younger patients and those without other comorbidities. Patients with solid cancer should be prioritised in vaccination campaigns and in tailored containment measurements.

CAL02, a novel antitoxin liposomal agent, in severe pneumococcal pneumonia: a first-in-human, double-blind, placebo-controlled, randomised trial.

BACKGROUND: Severe community-acquired pneumonia caused by Streptococcus pneumoniae is associated with high morbidity and mortality rates. CAL02, a novel antitoxin agent with an unprecedented mode of action, consists of liposomes that capture bacterial toxins known to dysregulate inflammation, cause organ damage, and impede immune defence. We aimed to assess the safety of CAL02 as an add-on therapy to antibiotics. METHODS: This randomised, double-blind, multicentre, placebo-controlled trial was done in ten intensive care units (ICUs) in France and Belgium (but only six units enrolled patients), in patients with severe community-acquired pneumococcal pneumonia who required ICU admission and had been identified as being infected with S pneumoniae. We randomly assigned participants in two stages-the first stage randomly assigned six patients (1:1) to either low-dose CAL02 or placebo, and the second stage randomly assigned 18 patients (14:4) to either high-dose CAL02 or placebo, and stratified in four blocks (4:1, 4:1, 3:1, and 3:1), in addition to standard of care. Block randomisation was done with a computer-generated random number list. Participants, investigators, other site study personnel, the sponsor, and the sponsor's designees involved in study management and monitoring were masked to the randomisation list and treatment assignment. Patients were treated with low-dose (4 mg/kg) or high-dose (16 mg/kg) CAL02 or placebo (saline), in addition to standard antibiotic therapy. Two intravenous doses of study treatment were infused, with a 24 h interval, at a concentration of 10 mg/mL, stepwise, over a maximum of 2 h on days 1 and 2. The primary objective of the study was to assess the safety and tolerability of low-dose and high-dose CAL02 in patients with severe community-acquired pneumonia treated with standard antibiotic therapy, and the primary analysis was done on the safety population (all patients who received at least one dose of the study treatment). Efficacy was a secondary outcome. This trial is registered with ClinicalTrials.gov, number NCT02583373. FINDINGS: Between March 21, 2016, and Jan 13, 2018, we screened 280 patients with community-acquired pneumonia. 19 patients were enrolled and randomly assigned, resulting in 13 patients in the CAL02 groups (three assigned to low-dose CAL02 and ten assigned to high-dose CAL02) and six in the placebo group. One patient randomly assigned to placebo was allocated to the wrong treatment group and received high-dose CAL02 instead of placebo. Thus, 14 patients received CAL02 (three received low-dose CAL02 and 11 received high-dose CAL02) and five patients received placebo, constituting the safety population. At baseline, the mean APACHE II score for the total study population was 21·5 (SD 4·9; 95% CI 19·3-23·7) and 11 (58%) of 19 patients had septic shock. Adverse events occurred in 12 (86%) of 14 patients in the CAL02 treatment groups combined and all five (100%) patients in the placebo group. Serious adverse events occurred in four (29%) of 14 patients in the CAL02 treatment groups combined and two (40%) of five patients in the placebo group. One non-serious adverse event (mild increase in triglycerides) in a patient in the high-dose CAL02 group was reported as related to study drug. However, analysis of the changes in triglyceride levels in the CAL02 groups compared with the placebo group revealed no correlation with administration of CAL02. No adverse events were linked to local tolerability events. All patients, apart from one who died in the low CAL02 group (death not related to the study drug) achieved clinical cure at the test of cure visit between days 15 and 22. The sequential organ failure assessment score decreased by mean 65·0% (95% CI 50·7-79·4) in the combined CAL02 groups compared with 29·2% (12·8-45·5) in the placebo group between baseline and day 8. INTERPRETATION: The nature of adverse events was consistent with the profile of the study population and CAL02 showed a promising safety profile and tolerability. However, the difference between high-dose and low-dose CAL02 could not be assessed in this study. Efficacy was in line with the expected benefits of neutralising toxins. The results of this study support further clinical development of CAL02 and provide a solid basis for a larger clinical study. FUNDING: Combioxin.

Proenkephalin A 119-159 (Penkid) Is an Early Biomarker of Septic Acute Kidney Injury: The Kidney in Sepsis and Septic Shock (Kid-SSS) Study.

Introduction: Sepsis is the leading cause of acute kidney injury (AKI) in critically ill patients. The Kidney in Sepsis and Septic Shock (Kid-SSS) study evaluated the value of proenkephalin A 119-159 (penkid)-a sensitive biomarker of glomerular function, drawn within 24 hours upon intensive care unit (ICU) admission and analyzed using a chemiluminescence immunoassay-for kidney events in sepsis and septic shock. Methods: The Kid-SSS study was a substudy of Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) (NCT02393781), a prospective, observational, multinational study including 583 patients admitted to the intensive care unit with sepsis or septic shock and a validation cohort of 525 patients from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study. The primary endpoint was major adverse kidney events (MAKEs) at day 7, composite of death, renal replacement therapy, and persistent renal dysfunction. The secondary endpoints included AKI, transient AKI, worsening renal function (WRF), and 28-day mortality. Results: Median age was 66 years (interquartile range 55-75), and 28-day mortality was 22% (95% confidence interval [CI] 19%-25%). Of the patients, 293 (50.3%) were in shock upon ICU admission. Penkid was significantly elevated in patients with MAKEs, persistent AKI, and WRF (median = 65 [IQR = 45-106] vs. 179 [114-242]; 53 [39-70] vs. 133 [79-196] pmol/l; and 70 [47-121] vs. 174 [93-242] pmol/l, all P < 0.0001), also after adjustment for confounding factors (adjusted odds ratio = 3.3 [95% CI = 1.8-6.0], 3.9 [95% CI = 2.1-7.2], and 3.4 [95% CI = 1.9-6.2], all P < 0.0001). Penkid increase preceded elevation of serum creatinine with WRF and was low in renal recovery. Conclusion: Admission penkid concentration was associated with MAKEs, AKI, and WRF in a timely manner in septic patients.

Optimizing ß-lactams treatment in critically-ill patients using pharmacokinetics/pharmacodynamics targets: are first conventional doses effective?

INTRODUCTION: The pharmacokinetic/pharmacodynamic index determining ß-lactam activity is the percentage of the dosing interval (%T) during which their free serum concentration remains above a critical threshold over the minimum inhibitory concentration (MIC). Regrettably, neither the value of %T nor that of the threshold are clearly defined for critically-ill patients. Areas covered: We review and assess the targets proposed for ß-lactams in critical illness by screening the literature since 1997. Depending on the study intention (clinical cure vs. suppression of resistance), targets proposed range from 20%T > 1xMIC to 100%T > 5xMIC. Assessment and comparative analysis of their respective clinical efficacy suggest that a value of 100%T > 4xMIC may be needed. Simulation studies, however, show that this target will not be reached at first dose for the majority of critically-ill patients if using the most commonly recommended doses. Expert commentary: Considering that critically-ill patients are highly vulnerable and likely to experience antibiotic underexposure, and because effective initial treatment is a key determinant of clinical outcome, we support the use of a target of 100%T > 4xMIC, which could not only maximize efficacy but also minimize emergence of resistance. Clinical and microbiological studies are needed to test for the feasibility and effectiveness of reaching such a demanding target.