Inhaled amikacin for severe Gram-negative pulmonary infections in the intensive care unit: current status and future prospects

Recently, the use of nebulized antibiotics in the intensive care unit, in particular amikacin, has been the subject of much discussion, owing to unconvincing results from the latest randomized clinical trials. Here, we examine and reappraise the evidence in favor and against this therapeutic strategy; we then discuss the potential factors that might have played a role in the negative findings of recent clinical trials. Also, we call attention to several factors that are seldom considered by study developers and regulatory agencies, to promote translational research in this field and improve the design of future randomized clinical trials

Procalcitonin and C-reactive protein to rule out early bacterial coinfection in COVID-19 critically ill patients.

Purpose Although the prevalence of community-acquired respiratory bacterial coinfection upon hospital admission in patients with coronavirus disease 2019 (COVID-19) has been reported to be < 5%, almost three-quarters of patients received antibiotics. We aim to investigate whether procalcitonin (PCT) or C-reactive protein (CRP) upon admission could be helpful biomarkers to identify bacterial coinfection among patients with COVID-19 pneumonia. Methods We carried out a multicentre, observational cohort study including consecutive COVID-19 patients admitted to 55 Spanish intensive care units (ICUs). The primary outcome was to explore whether PCT or CRP serum levels upon hospital admission could predict bacterial coinfection among patients with COVID-19 pneumonia. The secondary outcome was the evaluation of their association with mortality. We also conducted subgroups analyses in higher risk profile populations. Results Between 5 February 2020 and 21 December 2021, 4076 patients were included, 133 (3%) of whom presented bacterial coinfection. PCT and CRP had low area under curve (AUC) scores at the receiver operating characteristic (ROC) curve analysis [0.57 (95% confidence interval (CI) 0.51–0.61) and 0.6 (95% CI, 0.55–0.64), respectively], but high negative predictive values (NPV) [97.5% (95% CI 96.5–98.5) and 98.2% (95% CI 97.5–98.9) for PCT and CRP, respectively]. CRP alone was associated with bacterial coinfection (OR 2, 95% CI 1.25–3.19; p = 0.004). The overall 15, 30 and 90 days mortality had a higher trend in the bacterial coinfection group, but without significant difference. PCT ≥ 0.12 ng/mL was associated with higher 90 days mortality. Conclusion Our study suggests that measurements of PCT and CRP, alone and at a single time point, are not useful for ruling in or out bacterial coinfection in viral pneumonia by COVID-19.post-print1177 K

Procalcitonin and C-reactive protein to rule out early bacterial coinfection in COVID-19 critically ill patients

Although the prevalence of community-acquired respiratory bacterial coinfection upon hospital admission in patients with coronavirus disease 2019 (COVID-19) has been reported to be < 5%, almost three-quarters of patients received antibiotics. We aim to investigate whether procalcitonin (PCT) or C-reactive protein (CRP) upon admission could be helpful biomarkers to identify bacterial coinfection among patients with COVID-19 pneumonia. Methods: We carried out a multicentre, observational cohort study including consecutive COVID-19 patients admitted to 55 Spanish intensive care units (ICUs). The primary outcome was to explore whether PCT or CRP serum levels upon hospital admission could predict bacterial coinfection among patients with COVID-19 pneumonia. The secondary outcome was the evaluation of their association with mortality. We also conducted subgroups analyses in higher risk profile populations. Results: Between 5 February 2020 and 21 December 2021, 4076 patients were included, 133 (3%) of whom presented bacterial coinfection. PCT and CRP had low area under curve (AUC) scores at the receiver operating characteristic (ROC) curve analysis [0.57 (95% confidence interval (CI) 0.51–0.61) and 0.6 (95% CI, 0.55–0.64), respectively], but high negative predictive values (NPV) [97.5% (95% CI 96.5–98.5) and 98.2% (95% CI 97.5–98.9) for PCT and CRP, respectively]. CRP alone was associated with bacterial coinfection (OR 2, 95% CI 1.25–3.19; p = 0.004). The overall 15, 30 and 90 days mortality had a higher trend in the bacterial coinfection group, but without significant difference. PCT ≥ 0.12 ng/mL was associated with higher 90 days mortality. Conclusion: Our study suggests that measurements of PCT and CRP, alone and at a single time point, are not useful for ruling in or out bacterial coinfection in viral pneumonia by COVID-19

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

COVID-19; Mechanical ventilation; Ventilatory ratioCOVID-19; Respiració assistida; Relació ventilatòriaCOVID-19; Ventilación mecánica; Relación ventilatoriaBackground Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0–171.2] to 180.0 [135.4–227.9] mmHg and the ventilatory ratio from 1.73 [1.33–2.25] to 1.96 [1.61–2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01–1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01–1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93–1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation.Financial support was provided by the Instituto de Salud Carlos III de Madrid (COV20/00110, ISCIII), Fondo Europeo de Desarrollo Regional (FEDER), "Una manera de hacer Europa", and by the Centro de Investigación Biomedica En Red – Enfermedades Respiratorias (CIBERES). DdGC has received financial support from Instituto de Salud Carlos III (Miguel Servet 2020: CP20/00041), co-funded by European Social Fund (ESF)/”Investing in your future”

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0–171.2] to 180.0 [135.4–227.9] mmHg and the ventilatory ratio from 1.73 [1.33–2.25] to 1.96 [1.61–2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01–1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01–1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93–1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation.Instituto de Salud Carlos III de Madrid COV20/00110, ISCII

Higher frequency of comorbidities in fully vaccinated patients admitted to the ICU due to severe COVID-19: a prospective, multicentre, observational study

Severe COVID-19 disease requiring ICU admission is possible in the fully vaccinated population, especially in those with immunocompromised status and other comorbidities. Interventions to improve vaccine response might be necessary in this population.Peer ReviewedArticle signat per 23 autors/es: Anna Motos, Alexandre López-Gavín, Jordi Riera, Adrián Ceccato, Laia Fernández-Barat, Jesús F. Bermejo-Martin, Ricard Ferrer, David de Gonzalo-Calvo, Rosario Menéndez, Raquel Pérez-Arnal, Dario García-Gasulla, Alejandro Rodriguez, Oscar Peñuelas, José Ángel Lorente, Raquel Almansa, Albert Gabarrus, Judith Marin-Corral, Pilar Ricart, Ferran Roche-Campo, Susana Sancho Chinesta, Lorenzo Socias, Ferran Barbé, Antoni Torres on behalf of the CIBERESUCICOVID Project (COV20/00110, ISCIII).Postprint (published version

Lateral position during severe mono-lateral pneumonia: an experimental study

Patients with mono-lateral pneumonia and severe respiratory failure can be positioned in lateral decubitus, with the healthy lung dependent, to improve ventilation-perfusion coupling. Oxygenation response to this manoeuvre is heterogeneous and derecruitment of dependent lung has not been elucidated. Nine pigs (32.2 ± 1.2 kg) were sedated and mechanically ventilated. Mono-lateral right-sided pneumonia was induced with intrabronchial challenge of Pseudomonas aeruginosa. After 24 h, lungs were recruited and the animals were randomly positioned on right or left side. After 3 h of lateral positioning, the animals were placed supine; another recruitment manoeuvre was performed, and the effects of contralateral decubitus were assessed. Primary outcome was lung ultrasound score (LUS) of the dependent lung after 3-h lateral positioning. LUS of the left non-infected lung worsened while positioned in left-lateral position (from 1.33 ± 1.73 at baseline to 6.78 ± 4.49; p = 0.005). LUS of the right-infected lung improved when placed upward (9.22 ± 2.73 to 6.67 ± 3.24; p = 0.09), but worsened in right-lateral position (7.78 ± 2.86 to 13.33 ± 3.08; p < 0.001). PaO2/FiO2 improved in the left-lateral position (p = 0.005). In an animal model of right-lung pneumonia, left-lateral decubitus improved oxygenation, but collapsed the healthy lung. Right-lateral orientation further collapsed the diseased lung. Our data raise potential clinical concerns for the use of lateral position in mono-lateral pneumonia

Assessment of in vivo versus in vitro biofilm formation of clinical methicillin-resistant Staphylococcus aureus isolates from endotracheal tubes

Our aim was to demonstrate that biofilm formation in a clinical strain of methicillin-resistant Staphylococcus aureus (MRSA) can be enhanced by environment exposure in an endotracheal tube (ETT) and to determine how it is affected by systemic treatment and atmospheric conditions. Second, we aimed to assess biofilm production dynamics after extubation. We prospectively analyzed 70 ETT samples obtained from pigs randomized to be untreated (controls, n = 20), or treated with vancomycin (n = 32) or linezolid (n = 18). A clinical MRSA strain (MRSA-in) was inoculated in pigs to create a pneumonia model, before treating with antibiotics. Tracheally intubated pigs with MRSA severe pneumonia, were mechanically ventilated for 69 ± 16 hours. All MRSA isolates retrieved from ETTs (ETT-MRSA) were tested for their in vitro biofilm production by microtiter plate assay. In vitro biofilm production of MRSA isolates was sequentially studied over the next 8 days post-extubation to assess biofilm capability dynamics over time. All experiments were performed under ambient air (O2) or ambient air supplemented with 5% CO2. We collected 52 ETT-MRSA isolates (placebo N = 19, linezolid N = 11, and vancomycin N = 22) that were clonally identical to the MRSA-in. Among the ETT-MRSA isolates, biofilm production more than doubled after extubation in 40% and 50% under 5% CO2 and O2, respectively. Systemic antibiotic treatment during intubation did not affect this outcome. Under both atmospheric conditions, biofilm production for MRSA-in was at least doubled for 9 ETT-MRSA isolates, and assessment of these showed that biofilm production decreased progressively over a 4-day period after extubation. In conclusion, a weak biofilm producer MRSA strain significantly enhances its biofilm production within an ETT, but it is influenced by the ETT environment rather than by the systemic treatment used during intubation or by the atmospheric conditions used for bacterial growth

Development of a model for anemia of inflammation that is relevant to critical care

Background: Anemia of inflammation (AI) is common in critically ill patients. Although this syndrome negatively impacts the outcome of critical illness, understanding of its pathophysiology is limited. Also, new therapies that increase iron availability for erythropoiesis during AI are upcoming. A model of AI induced by bacterial infections that are relevant for the critically ill is currently not available. This paper describes the development of an animal model for AI that is relevant for critical care research. Results: In experiments with rats, the rats were inoculated either repeatedly or with a slow release of Streptococcus pneumoniae or Pseudomonas aeruginosa. Rats became ill, but their hemoglobin levels remained stable. The use of a higher dose of bacteria resulted in a lethal model. Then, we turned to a model with longer disease duration, using pigs that were supported by mechanical ventilation after inoculation with P. aeruginosa. The pigs became septic 12 to 24 h after inoculation, with a statistically significant decrease in mean arterial pressure and base excess, while heart rate tended to increase. Pigs needed resuscitation and vasopressor therapy to maintain a mean arterial pressure > 60 mmHg. After 72 h, the pigs developed anemia (baseline 9.9 g/dl vs. 72 h, 7.6 g/dl, p = 0.01), characterized by statistically significant decreased iron levels, decreased transferrin saturation, and increased ferritin. Hepcidin levels tended to increase and transferrin levels tended to decrease. Conclusions: Using pathogens commonly involved in pulmonary sepsis, AI could not be induced in rats. Conversely, in pigs, P. aeruginosa induced pulmonary sepsis with concomitant AI. This AI model can be applied to study the pathophysiology of AI in the critically ill and to investigate the effectivity and toxicity of new therapies that aim to increase iron availability. Keywords: Anemia of inflammation; Animal model; ICU; Infection; Iron

Diagnostic Value of Endotracheal Aspirates Sonication on Ventilator-Associated Pneumonia Microbiologic Diagnosis

Microorganisms are able to form biofilms within respiratory secretions. Methods to disaggregate such biofilms before utilizing standard, rapid, or high throughput diagnostic technologies may aid in pathogen detection during ventilator associated pneumonia (VAP) diagnosis. Our aim was to determine if sonication of endotracheal aspirates (ETA) would increase the sensitivity of qualitative, semi-quantitative, and quantitative bacterial cultures in an animal model of pneumonia caused by Pseudomonasaeruginosa or by methicillin resistant Staphylococcusaureus (MRSA). MATERIAL AND METHODS: P.aeruginosa or MRSA was instilled into the lungs or the oropharynx of pigs in order to induce severe VAP. Time point assessments for qualitative and quantitative bacterial cultures of ETA and bronchoalveolar lavage (BAL) samples were performed at 24, 48, and 72 h after bacterial instillation. In addition, at 72 h (autopsy), lung tissue was harvested to perform quantitative bacterial cultures. Each ETA sample was microbiologically processed with and without applying sonication for 5 min at 40 KHz before bacterial cultures. Sensitivity and specificity were determined using BAL as a gold-standard. Correlation with BAL and lung bacterial burden was also determined before and after sonication. Assessment of biofilm clusters and planktonic bacteria was performed through both optical microscopy utilizing Gram staining and Confocal Laser Scanning Microscopy utilizing the LIVE/DEAD®BacLight kit. RESULTS: 33 pigs were included, 27 and 6 from P.aeruginosa and MRSA pneumonia models, respectively. Overall, we obtained 85 ETA, 69 (81.2%) from P.aeruginosa and 16 (18.8%) from MRSA challenged pigs. Qualitative cultures did not significantly change after sonication, whereas quantitative ETA cultures did significantly increase bacterial counting. Indeed, sonication consistently increased bacterial burden in ETAs at 24, 48, and 72 h after bacterial challenge. Sonication also improved sensitivity of ETA quantitative cultures and maintained specificity at levels previously reported and accepted for VAP diagnosis. CONCLUSION: The use of sonication in ETA respiratory samples needs to be clinically validated since sonication could potentially improve pathogen detection before standard, rapid, or high throughput diagnostic methods used in routine microbial diagnostics