A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilatorassociated pneumonia

INTRODUCTION: The aim of this study was to compare a 7-day course of doripenem to a 10-day course of imipenem-cilastatin for ventilator-associated pneumonia (VAP) due to Gram-negative bacteria. METHODS: This was a prospective, double-blinded, randomized trial comparing a fixed 7-day course of doripenem one gram as a four-hour infusion every eight hours with a fixed 10-day course of imipenem-cilastatin one gram as a one-hour infusion every eight hours (April 2008 through June 2011). RESULTS: The study was stopped prematurely at the recommendation of the Independent Data Monitoring Committee that was blinded to treatment arm assignment and performed a scheduled review of data which showed signals that were close to the pre-specified stopping limits. The final analyses included 274 randomized patients. The clinical cure rate at the end of therapy (EOT) in the microbiological intent-to-treat (MITT) population was numerically lower for patients in the doripenem arm compared to the imipenem-cilastatin arm (45.6% versus 56.8%; 95% CI, -26.3% to 3.8%). Similarly, the clinical cure rate at EOT was numerically lower for patients with Pseudomonas aeruginosa VAP, the most common Gram-negative pathogen, in the doripenem arm compared to the imipenem-cilastatin arm (41.2% versus 60.0%; 95% CI, -57.2 to 19.5). All cause 28-day mortality in the MITT group was numerically greater for patients in the doripenem arm compared to the imipenem-cilastatin arm (21.5% versus 14.8%; 95% CI, -5.0 to 18.5) and for patients with P. aeruginosa VAP (35.3% versus 0.0%; 95% CI, 12.6 to 58.0). CONCLUSIONS: Among patients with microbiologically confirmed late-onset VAP, a fixed 7-day course of doripenem was found to have non-significant higher rates of clinical failure and mortality compared to a fixed 10-day course of imipenem-cilastatin. Consideration should be given to treating patients with VAP for more than seven days to optimize clinical outcome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT0058969

Clinical phenotypes in adult patients with bronchiectasis

Bronchiectasis is a heterogeneous disease. This study aimed at identifying discrete groups of patients with different clinical and biological characteristics and long-term outcomes. This was a secondary analysis of five European databases of prospectively enrolled adult outpatients with bronchiectasis. Principal component and cluster analyses were performed using demographics, comorbidities, and clinical, radiological, functional and microbiological variables collected during the stable state. Exacerbations, hospitalisations and mortality during a 3-year follow-up were recorded. Clusters were externally validated in an independent cohort of patients with bronchiectasis, also investigating inflammatory markers in sputum. Among 1145 patients (median age 66 years; 40% male), four clusters were identified driven by the presence of chronic infection with Pseudomonas aeruginosa or other pathogens and daily sputum: "Pseudomonas" (16%), "Other chronic infection" (24%), "Daily sputum" (33%) and "Dry bronchiectasis" (27%). Patients in the four clusters showed significant differences in terms of quality of life, exacerbations, hospitalisations and mortality during follow-up. In the validation cohort, free neutrophil elastase activity, myeloperoxidase activity and interleukin-1\u3b2 levels in sputum were significantly different among the clusters. Identification of four clinical phenotypes in bronchiectasis could favour focused treatments in future interventional studies designed to alter the natural history of the disease

The impact of empiric antimicrobial therapy with a β-lactam and fluoroquinolone on mortality for patients hospitalized with severe pneumonia

INTRODUCTION: National clinical practice guidelines have recommended specific empiric antimicrobial regimes for patients with severe community-acquired pneumonia. However, evidence confirming improved mortality with many of these regimes is lacking. Our aim was to determine the association between the empiric use of a β-lactam with fluoroquinolone, compared with other recommended antimicrobial therapies, and mortality in patients hospitalized with severe community-acquired pneumonia. METHODS: A retrospective observational study was conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of community-acquired pneumonia and had a chest X-ray and a discharge ICD-9 diagnosis consistent with this. Subjects were excluded if they received 'comfort measures only' during the admission, had been transferred from another acute care hospital, did not meet criteria for severe pneumonia, or were treated with non-guideline-concordant antibiotics. A multivariable logistic regression model was used to assess the association between 30-day mortality and the use of a β-lactam antibiotic with a fluoroquinolone compared with other guideline-concordant therapies, after adjustment for potential confounders including a propensity score. RESULTS: Data were abstracted on 172 subjects at the two hospitals. The mean age was 63.5 years (SD 15.0). The population was 88% male; 91% were admitted through the emergency department and 62% were admitted to the intensive care unit within the first 24 hours after admission. Mortality was 19.8% at 30 days. After adjustment for potential confounders the use of a β-lactam with a fluoroquinolone (odds ratio 2.71, 95% confidence interval 1.2 to 6.1) was associated with increased mortality. CONCLUSION: The use of initial empiric antimicrobial therapy with a β-lactam and a fluoroquinolone was associated with increased short-term mortality for patients with severe pneumonia in comparison with other guideline-concordant antimicrobial regimes. Further research is needed to determine the range of appropriate empiric antimicrobial therapies for patients with severe community-acquired pneumonia

Impact of prior outpatient antibiotic use on mortality for community acquired pneumonia: a retrospective cohort study

Abstract Background The purpose of this study was to examine whether prior outpatient antibiotic use is associated with increased 30-day mortality, after adjusting for potential confounders, for those subsequently hospitalized with pneumonia. Methods A retrospective cohort study conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, and had a chest x-ray consistent with, community-acquired pneumonia. Our primary analysis was a multivariable logistic regression with the dependent variable of 30-day mortality. Results Data was abstracted on 733 subjects at the two hospitals. Mortality was 8.1% at 30-days. At presentation, 55% of subjects were low risk, 33% were moderate risk, and 12% were high risk. In our cohort 17% (n = 128) of subjects received antibiotics within 30-days of presentation. Unadjusted mortality for those who had received prior antibiotics was 7.0% vs. 8.3% for those who had not (p = 0.6). In the multivariable analysis prior use of antibiotics (odds ratio 0.98, 95% confidence interval 0.5–2.1) was not significantly associated with 30-day mortality. Conclusion Receipt of prior outpatient antibiotics is not significantly associated with 30-day mortality for patients hospitalized with pneumonia. Our study supports current efforts to increase the number of patients with pneumonia who are treated as outpatients.</p

Using Cluster Analysis of Cytokines to Identify Patterns of Inflammation in Hospitalized Patients with Community-acquired Pneumonia:A Pilot Study

Purpose: Patients with severe community-acquired pneumonia (CAP) are believed to have an exaggerated inflammatory response to bacterial infection. Therapies aiming to modulate the inflammatory response have been largely unsuccessful, perhaps reflecting that CAP is a heterogeneous disorder that cannot be modulated by a single anti-inflammatory approach. We hypothesize that the host inflammatory response to pneumonia may be characterized by distinct cytokine patterns, which can be harnessed for personalized therapies. Methods: Here, we use hierarchical cluster analysis of cytokines to examine if patterns of inflammatory response in 13 hospitalized patients with CAP can be defined. This was a secondary data analysis of the Community-Acquired Pneumonia Inflammatory Study Group (CAPISG) database. The following cytokines were measured in plasma and sputum on the day of admission: interleukin (IL)-1β, IL-1 receptor antagonist (IL-1ra), IL-6, CXCL8 (IL-8), IL-10, IL-12p40, IL-17, interferon (IFN)γ, tumor necrosis factor (TNF)α, and CXCL10 (IP-10). Hierarchical agglomerative clustering algorithms were used to evaluate clusters of patients within plasma and sputum cytokine determinations. Results: A total of thirteen patients were included in this pilot study. Cluster analysis identified distinct inflammatory response patterns of cytokines in the plasma, sputum, and the ratio of plasma to sputum. Conclusions: Inflammatory response patterns in plasma and sputum can be identified in hospitalized patients with CAP. Characterization of the local and systemic inflammatory response may help to better discriminate patients for enrollment into clinical trials of immunomodulatory therapies

Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling

Rationale: Up to one-third of patients hospitalized with pneumococcal pneumonia experience major adverse cardiac events (MACE) during or after pneumonia. In mice, Streptococcus pneumoniae caninvade themyocardium, induce cardiomyocyte death, and disrupt cardiac function following bacteremia, but it is unknown whether the same occurs in humans with severe pneumonia. Objectives: We sought to determine whether S. pneumoniae can (1) translocate the heart, (2) induce cardiomyocyte death, (3) causeMACE, and (4) induce cardiac scar formation after antibiotic treatment during severe pneumonia using a nonhuman primate (NHP) model. Methods: We examined cardiac tissue from six adult NHPs with severe pneumococcal pneumonia and three uninfected control animals. Three animals were rescued with antibiotics (convalescent animals). Electrocardiographic, echocardiographic, and serum biomarkers of cardiac damage were measured (troponin T, N-terminal pro-brain natriuretic peptide, and heart-type fatty acid binding protein). Histological examination included hematoxylin and eosin staining, immunofluorescence, immunohistochemistry, picrosirius red staining, and transmission electron microscopy. Immunoblots were used to assess the underlying mechanisms. Measurements and Main Results: Nonspecific ischemic alterations were detected by electrocardiography and echocardiography. Serum levels of troponin T and heart-type fatty acid binding protein were increased (P,0.05) after pneumococcal infection in both acutely ill and convalescent NHPs. S. pneumoniae was detected in the myocardium of all NHPs with acute severe pneumonia. Necroptosis and apoptosis were detected in the myocardium of both acutely ill and convalescent NHPs. Evidence of cardiac scar formation was observed only in convalescent animals by transmission electron microscopy and picrosirius red staining. Conclusions: S. pneumoniae invades the myocardium and induces cardiac injury with necroptosis and apoptosis, followed by cardiac scarring after antibiotic therapy, in anNHP model of severe pneumonia

Diagnostic and prognostic trajectories of interstitial lung diseases after the multidisciplinary discussion

Background: The 2018 guidelines on the diagnosis of idiopathic pulmonary fibrosis (IPF) conditionally recommend multidisciplinary discussion (MDD) for diagnostic decision-making. However, limited data concerning the diagnostic impact of MDD on interstitial lung diseases (ILDs) are available. Objectives: The objective of this prospective study was to assess the impact of MDD at a tertiary referral ILD center on diagnostic trajectories, prognosis, and identification of potential treatable traits in ILD management. Design: This prospective study enrolled all consecutive adult ILD patients referred for MDD to a tertiary academic center in San Antonio, TX, USA from January 2017 to May 2020. The subjects were followed during a 3-year follow-up period after the MDD. Methods: Patients were stratified into three groups according to the pre-MDD diagnosis: unspecified ILD, IPF, and not IPF, and compared to the re-stratification post-MDD diagnosis into: unclassifiable ILD, IPF, and not IPF. The primary outcome was the percentage change in diagnostic trajectories after the MDD discussion. Results: A total of 201 ILD patients (61.7% male; mean (DS) age: 67.2 (10.4) years) were included in the study. The total diagnostic trajectory change occurred in 122 (60.7%) patients. The diagnostic trajectories changed in 40 (46.5%) patients in the IPF group and 8 (19.5%) in the non-IPF group (p-value = 0.0003). Patients with pre-MDD unspecified-ILD were classified as not-IPF in 32.4% (n = 24), IPF in 23% (n = 17), and unclassifiable-ILD in 44.6% (n = 33) post-MDD. Considering the post-MDD diagnosis, differences in mortality were detected among the three groups (p = 0.037). Conclusion: Our results suggest that MDD has a significant impact not only on the diagnostic trajectories (DT) but also on the prognosis of patients with ILDs

Análisis de severidad y criterios de hospitalización en pacientes con neumonía adquirida en la comunidad

a neumonía adquirida en la comunidad es una enfermedad que causa alta morbilidad, mortalidad y costos. Este artículo tiene como finalidad discutir los diferentes métodos de evaluación de severidad de la enfermedad, para determinar el mejor sitio para el tratamiento de los pacientes. Utilizamos un caso clínico ficticio a manera de ejercicio para aplicar las diferentes herramientas: PSI, CURB y CURB-65. Sugerimos el uso tanto del CURB como del CURB-65, por su fácil aplicación y buena efectividad en la práctica clínica. La presencia de dos o más de los criterios clínicos: (Confusión, BUN > 19,6 mg/dL [7 mmol/L], frecuencia respiratoria ≥ 30/min, e hipotensión arterial [presión arterial sistólica o diastólica < 90/60 mmHg]) sugieren que el paciente debe ser manejado en el hospital. Estos métodos no tienen la función de reemplazar, sino de reforzar objetivamente el criterio clínico en la toma de decisión del lugar apropiado de tratamiento del paciente con neumonía adquirida en la comunidad. ABSTRACT Community acquired pneumonia is a disease with high morbidity, mortality and cost. Our goal is to discuss the available severity of illness scores, in order to define the best place for patient treatment. We used a fictional clinical case to serve as an exercise in which we apply the PSI, CURB and CURB-65 tools. We recommend the use of both the CURB and CURB-65 because their practicality and good effectiveness in clinical practice. The presence of two or more of the following criteria (Confusion, blood Urea nitrogen > 19.6 mg/dL (7 mmol/L), Respiratory rate > 30/min and Blood pressure < 90/60 mmHg) suggests that the patient should be managed in the hospital setting. These objective methods do are not intended to replace, but rather to reinforce the clinical the decision making capacity in regard of the place to treat a patient with community acquired pneumonia