[Pharmacokinetic modifications and pharmacokinetic/pharmacodynamic optimization of beta-lactams in ICU]. / Modifications pharmacocinétiques et optimisation pharmacocinétique/pharmacodynamique des bêta-lactamines en réanimation.

Pharmacokinetic modifications in critically ill patients and those induced by ICU therapeutics raise a lot of issues about antibiotic dose adaptation. Beta-lactams are anti-infectious widely used in ICU. Frequent beta-lactam underdoses induce a risk of therapeutic failure potentially lethal and of emergence of bacterial resistance. Overdoses expose to a neurotoxic and nephrotoxic risk. Therefore, an understanding of pharmacokinetics modifications appears to be essential. A global pharmacokinetic/pharmacodynamic approach is required, including use of prolonged or continued beta-lactam infusions to optimise probability of pharmacokinetic/pharmacodynamic target attainment. Beta-lactam therapeutic drug monitoring should also be considered. Experts agree to target a free plasma betalactam concentration above four times the MIC of the causative bacteria for 100 % of the dosing interval. Bayesian methods could permit individualized doses adaptations.

The role of the critical care pharmacist during the COVID-19 pandemic.

On January 4 2020, the World Health Organization (WHO) reported the emergence of a cluster of pneumonia cases in Wuhan, China due to a new coronavirus, the SARS-CoV-2. A few weeks later, hospitals had to put in place a series of drastic measures to deal with the massive influx of suspected COVID-19 (COronaroVIrus Disease) patients while securing regular patient care, in particular in the intensive care units (ICU). Since March 12th, 77 of the 685 COVID-19 patients admitted to our hospital required hospitalization in the ICU. What are the roles and the added-value of the critical care pharmacist during this period? His missions have evolved although they have remained focused on providing health services for the patients. Indeed, integrated into a steering committee created to organize the crisis in the intensive care units, the role of the clinical pharmacist was focused on the organization and coordination between ICU and the pharmacy, the implementation of actions to secure practices, to train new professionals and the adaptation of therapeutic strategies. He participated to literature monitoring and increased his involvement in the clinical research team. He provided a link between the ICU and the pharmacy thanks to his knowledges of practices and needs.

Efficacy and safety of aerosolized intra-tracheal dornase alfa administration in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may trigger severe pneumonia in coronavirus disease of 2019 (COVID-19) patients through release of damage-associated molecular patterns (DAMPs) and recruitment of neutrophils in the lungs. Activated neutrophils induce inflammation and severe alveolar injury by releasing neutrophil extracellular traps (NETs). The backbones of many DAMPs and NETs are made of extracellular, cell-free DNA decorated with highly toxic compounds such as elastase, myeloperoxidase and citrullinated histones. Dornase alfa is a FDA-approved recombinant human DNAse 1 for the treatment of cystic fibrosis, which cleaves extracellular DNA and may break up cell-free DNA, loosening sticky mucus in the distal airways and reducing NETs-induced toxicity on alveolar pneumocytes. The COVIDornase trial intends to define the impact of aerosolized intra-tracheal dornase alfa administration on the severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19 patients. This drug might make lung mucus thinner and looser, promoting improved clearance of secretions and reduce extracellular double-stranded DNA-induced hyperinflammation in alveoli, preventing further damage to the lungs. TRIAL DESIGN: COVIDornase is a prospective, randomized, controlled, 2-arm (1:1 ratio), multicentric, open-label clinical trial. PARTICIPANTS: The study will recruit mechanically ventilated patients hospitalized in the intensive care unit (ICU) in the recruiting centres (at the time of writing: The Rothschild foundation hospital in Paris, the Strasbourg university hospitals, and Metz-Thionville hospital) who have been diagnosed with COVID-19 and meet ARDS criteria. INCLUSION CRITERIA: - Adult patient (age ≥ 18 years old); - Hospitalized in ICU; - With severe COVID-19 pneumonia and ARDS according to Berlin criteria (PaO2/FiO2 < 300 and PEEP > 5 cmH2O); - Intubated for less than 8 days; - With an anticipated duration of mechanical ventilation > 48 hours; - Carrier of an arterial catheter; - For whom 4 PaO2/FiO2 values over the preceding 24 hours are available; NON-INCLUSION CRITERIA: - Known hypersensitivity to dornase alfa or any of its excipients; - Pregnant or breastfeeding status; - Patient under legal protection. INTERVENTION AND COMPARATOR: Intervention 1, Study group Dornase alfa (Pulmozyme®, Roche, Switzerland) will be administered by aerosol, at a dose of 2500 IU twice daily, 12 hours apart, for 7 consecutive days, using a vibrating mesh nebulizer (Aerogen Solo®, Aerogen, Ireland). The remainder of the management will be performed in accordance with good clinical practice, including mechanical ventilation (protective ventilation, PEEP > 5 cmH2O, tracheal balloon pressure check every 4 hours or automatic device, 30° head of the bed elevation, tidal volume 6-8mL/kg, plateau pressure < 30 cmH2O), neuromuscular blockers if necessary, prone position if PaO2/FiO2 < 150, early enteral nutrition, glycemic control and a sedation protocol based on the RASS score. Intervention 2, Comparator Patients will receive usual care in accordance with good practice (as detailed above), without aerosols. MAIN OUTCOMES: The primary outcome is the occurrence of at least one grade improvement between D0 (inclusion) and D7 in the ARDS scale severity (Berlin criteria). For instance from "severe" to "moderate" or from "moderate" to "mild". RANDOMISATION: All consecutive patients meeting the inclusion criteria will be randomised 1:1 using an eCRF-based, computer-generated randomisation table, either to the dornase alfa arm or to the control arm. An interim analysis will be performed after inclusion of 20 patients. Inclusions may be stopped at the interim analysis per data safety and monitoring board (DSMB) advice, if statistical analyses conclude on the futility or efficacy of the intervention or by other DSMB decision. BLINDING (MASKING): The participants and caregivers will not be blinded to study group assignment. Those assessing the outcomes will be blinded to study group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Fifty patients will be randomized to each group, 100 patients in total. TRIAL STATUS: Protocol version number 2, April 29th, 2020. Recruitment is ongoing. The trial started recruitment on the 21st April 2020. We estimate recruitment will finish August 21st 2020. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov on 21 April 2020, updated on 8 May 2020. Trial registration number is NCT04355364. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated. This Letter serves as a summary of the key elements of the full protocol.

Invasive pulmonary aspergillosis in an ICU patient with Legionnaires' disease: A diagnostic challenge.

Aspergillus fumigatus can cause a wide range of diseases, from hypersensitivity to invasive infection. Invasive disease usually occurs in severely immunocompromised patients with deep and prolonged neutropenia. It is a less well-recognized complication in critically ill patients without traditional risk factors. We describe a case of early invasive pulmonary aspergillosis (IPA) secondary to Legionella pneumophila serogroup 1 pneumonia in a patient on an intensive care unit (ICU). In addition to commonly accepted risk factors for IPA in ICU patients, we hypothesis that L. pneumophilia pneumonia could enhance this type of infection. We also reviewed all published cases of coinfection with L. pneumophila and A. fumigatus to assess whether Legionnaires' disease could be a risk factor for IPA.

Does high antibiotic consumption still reflect bad practices?

OBJECTIVE: The authors had for aim to assess the quality of antibiotic prescription in an intensive care unit because of their high rate of consumption. DESIGN: A prospective 5-month study was made of the first 50 prescriptions of ciprofloxacin, levofloxacin, teicoplanin, vancomycin, and imipenem. Treatment was considered adequate at day 5 if the indication was relevant, with the right doses, and if the prescription was adapted to the antibiogram. RESULTS: Fifty treatments were evaluated (38 patients included). Eighty-four percent (42/50) was adequate at day 5. Glycopeptides and fluoroquinolones accounted for 2/3 of prescriptions. The absence of de-escalation was the most common mistake. The severity of presentations was evident with a mean SSI at 68 (22-113), and a mean BMI at 28 (18.5 - 50). Eighty-four percent (32/38) of patients were exposed to invasive devices, 47% died in the ICU. DISCUSSION: Most prescriptions were adequate. The patient profile could explain the high rate of antibiotic consumption. Bacteriological monitoring revealed an increased prevalence of resistant bacteria, which could explain a high rate of consumption along with adaptation of the dose to overweight. De-escalation, using aminosides more frequently, and shorter prescribed courses of fluoroquinolones should improve consumption rates does not always reflect bad practices, but may be adequate when considering bacterial ecology and patient profile.

[Prospective assessment of glycopeptides prescriptions in a general hospital]. / Evaluation prospective de la prescription des glycopeptides dans un hôpital général.

OBJECTIVE: The authors had for aim to analyze the indications, quality, and volumes of glycopeptide (GP) prescriptions in all in-patient units of a general hospital. CLINICAL MATERIAL AND METHODOLOGY: A 4 month prospective study assessed the compliance of curative and prophylactic treatment prescriptions administered according to guidelines. The assessment criteria were as follows: prescription indicated or not, prescription modalities (administration of loading dose, performing of serum tests, dosage appropriateness, appropriateness with antibiogram data when available). RESULTS: Over the 46 assessed prescriptions, 84.7% were curative treatments (N = 39), whereas 15.2% (N = 7) were written out for surgical antibioprophylaxis. The prescription incidence and density were, respectively, 0.60 prescription/100 admissions and 20.8 DDJ/1000 hospitalization days, i.e. 24% of the total antibiotics budget. Prescriptions were always indicated for surgical antibioprophylaxis, but met standards in only 14% of cases. As for curative prescriptions, treatments were appropriate in 56.5% of cases, but only 18% met standards. GP use modalities proved incorrect at various levels: non existing load dose and lack of serum tests, subinhibiting daily doses, no dose lowering when possible, exaggerated duration of surgical antibioprophylaxis. Average GP serum levels were 16 mg/L and were higher than the target level in no more than 40% of properly prescribed treatments. CONCLUSION: Prescription modalities and treatment monitoring must be improved, given the development of bacterial resistance.

[Prognosis of severe community-acquired pneumonia in alcoholic patients hospitalized in intensive care]. / Pronostic des pneumopathies communautaires graves chez des patients éthyliques chroniques hospitalisés en réanimation.

INTRODUCTION: The purpose of our study was to determine prognosis factors of alcoholic patients hospitalised in an intensive care unit with severe community-acquired pneumonia (SCAP). METHOD: Chronic alcoholism was defined by intake of pur alcohol more than 36 g per day for more than one year and severe community-acquired pneumonia by the criteria of the American Thoracic Society. RESULTS: 50 patients were included. Mortality rate was 48% in the department and 68% at two months after dismissal from intensive care. 1 Yen percent of patients were admitted in a state of shock (100% mortality). The most frequent pathogen was Streptococus pneumoniae (38%). The major complications were: 24% acute respiratory distress syndrome (ARDS), 18% multi-organ failure, 48% disseminated intravascular coagulopathy (DIC), 48% pulmonary superinfection. Antibiotherapy was not conform to current guidelines in 20% of cases and hence led to 90% death. DISCUSSION: Mortality rate was higher than in other studies. Bad prognosis factors were identified: severe state on admission, shock on admission or subsequently, non adapted initial antibiotherapy, Child's score B and C, Streptococus pneumoniae, complications: ARDS, superinfections, coagulopathy, multi organ failure.