Influenza and bacterial pneumonia - constant companions

Sequential or concomitant influenza and bacterial pneumonia are two common syndromes seen in community-acquired pneumonia. Inadequacies of diagnostic testing make separating simple pneumonia with either bacteria or influenza from concomitant or sequential influenza with both microorganisms difficult, although the novel 2009 H1N1 epidemic may improve the availability of molecular testing for viruses. Given the frequency of viral pneumonia and diagnostic limitations, empirical antivirals may be underutilized in community-acquired pneumonia. Thankfully, increasingly effective vaccines appear to disrupt this synergistic relationship

High Discordance of Chest X-ray and CT for Detection of Pulmonary Opacities in ED Patients: Implications for Diagnosing Pneumonia

Objective To evaluate the diagnostic performance of chest x-ray (CXR) compared to computed tomography (CT) for detection of pulmonary opacities in adult emergency department (ED) patients. Methods We conducted an observational cross-sectional study of adult patients presenting to 12 EDs in the United States from July 1, 2003, through November 30, 2006, who underwent both CXR and chest CT for routine clinical care. CXRs and CT scans performed on the same patient were matched. CXRs and CT scans were interpreted by attending radiologists and classified as containing pulmonary opacities if the final radiologist report noted opacity, infiltrate, consolidation, pneumonia, or bronchopneumonia. Using CT as a criterion standard, the diagnostic test characteristics of CXR to detect pulmonary opacities were calculated. Results The study cohort included 3423 patients. Shortness of breath, chest pain and cough were the most common complaints, with 96.1% of subjects reporting at least one of these symptoms. Pulmonary opacities were visualized on 309 (9.0%) CXRs and 191 (5.6 %) CT scans. CXR test characteristics for detection of pulmonary opacities included: sensitivity 43.5% (95% CI, 36.4%-50.8%); specificity 93.0% (95% CI, 92.1%-93.9%); positive predictive value 26.9% (95% CI, 22.1%-32.2%); and negative predictive value 96.5% (95% CI, 95.8%-97.1%). Conclusion In this multicenter cohort of adult ED patients with acute cardiopulmonary symptoms, CXR demonstrated poor sensitivity and positive predictive value for detecting pulmonary opacities. Reliance on CXR to identify pneumonia may lead to significant rates of misdiagnosis

Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: A Mouse MRSA Pneumonia Model

Background: Linezolid (LZD) is beneficial to patients with MRSA pneumonia, but whether and how LZD influences global host lung immune responses at the mRNA level during MRSA-mediated pneumonia is still unknown.Methods: A lethal mouse model of MRSA pneumonia mediated by USA300 was employed to study the influence of LZD on survival, while the sublethal mouse model was used to examine the effect of LZD on bacterial clearance and lung gene expression during MRSA pneumonia. LZD (100mg/kg/day, IP) was given to C57Bl6 mice for three days. On Day 1 and Day 3 post infection, bronchoalveolar lavage fluid (BALF) protein concentration and levels of cytokines including IL6, TNFα, IL1β, Interferon-γ and IL17 were measured. In the sublethal model, left lungs were used to determine bacterial clearance and right lungs for whole-genome transcriptional profiling of lung immune responses.Results: LZD therapy significantly improved survival and bacterial clearance. It also significantly decreased BALF protein concentration and levels of cytokines including IL6, IL1β, Interferon-γ and IL17. No significant gene expression changes in the mouse lungs were associated with LZD therapy.Conclusion: LZD is beneficial to MRSA pneumonia, but it does not modulate host lung immune responses at the transcriptional level.</p

a cohort study

Funding: This work was supported by grants from the National Institutes of Health (U19AI135964, P30AG059988), with institutional support from UL1TR001422. The funding agency played no role in the study design, collection of data, analysis, or interpretation of data.The impact of multidrug-resistant (MDR) colonization and MDR infection in critically ill cirrhosis patients remains unclear. We assessed the association of MDR colonization and MDR infection with these patients' survival. Observational cohort study including adult cirrhosis patients admitted to 5 intensive care units at Northwestern Memorial Hospital (Chicago, Illinois, USA) on January 1, 2010, to December 31, 2017. Patients admitted for elective liver transplant or with previous liver transplant were excluded. Patients were screened for MDR colonization on intensive care unit admission. Infection diagnoses during the intensive care unit stay were considered. The primary endpoint was hospital transplant-free survival. Among 600 patients included, 362 (60%) were men and median (interquartile range) age was 58.0 (49.0, 64.0) years. Median (interquartile range) Model for End-stage Liver Disease, Sequential Organ Failure Assessment, and Chronic Liver Failure-Acute-on-Chronic Liver Failure scores on intensive care unit day 1 were 28.0 (20.0, 36.0), 9.0 (6.0, 13.0), and 55.0 (48.0, 64.0), respectively. Overall, 76 (13%) patients were transplanted and 443 (74%) survived the hospital stay. Infections were diagnosed in 347 (58%) patients: pneumonia in 197 (33%), urinary tract infection in 119 (20%), peritonitis in 93 (16%), bloodstream infection in 99 (16%), Clostridium difficile colitis in 9 (2%), and catheter tip infection in 7 (1%). MDR colonization and MDR infection were identified in 200 (33%) and 69 (12%) patients, respectively. MDR colonization was associated with MDR infection (p < 0.001). MDR colonization or MDR infection was associated with higher number and duration of antibiotics (p < 0.001). Following adjustment for covariables (age, sex, etiology, portal hypertension, and Sequential Organ Failure Assessment score), MDR colonization [OR (95% CI), 0.64 (0.43, 0.95)] or MDR infection [adjusted OR (95% CI), 0.22 (0.12, 0.40)] were independently associated with lower transplant-free survival. Among critically ill cirrhosis patients, MDR colonization or MDR infection portended a worse prognosis.publishersversionpublishe

Common chronic conditions do not affect performance of cell cycle arrest biomarkers for risk stratification of acute kidney injury

Background Identification of acute kidney injury (AKI) can be challenging in patients with underlying chronic disease, and biomarkers often perform poorly in this population. In this study we examined the performance characteristics of the novel biomarker panel of urinary tissue inhibitor of metalloproteinases-2 (TIMP2) and insulin-like growth factor-binding protein 7 ([IGFBP7]) in patients with a variety of comorbid conditions. Methods We analyzed data from two multicenter studies of critically ill patients in which [TIMP2]•[IGFBP7] was validated for prediction of Kidney Disease: Improving Global Outcomes (KDIGO) Stage 2 or 3 AKI within 12 h. We constructed receiver operating characteristic (ROC) curves for AKI prediction both overall and by comorbid conditions common among patients with AKI, including diabetes mellitus, congestive heart failure (CHF) and chronic kidney disease (CKD). Results In the overall cohort of 1131 patients, 139 (12.3%) developed KDIGO Stage 2 or 3 AKI. [TIMP2]•[IGFBP7] was significantly higher in AKI versus non-AKI patients, both overall and within each comorbidity subgroup. The AUC for [TIMP2]•[IGFBP7] in predicting AKI was 0.81 overall. Higher AUC was noted in patients with versus without CHF (0.89 versus 0.79; P = 0.026) and CKD (0.91 versus 0.80; P = 0.024). Conclusions We observed no significant impairment in the performance of cell cycle arrest biomarkers due to the presence of chronic comorbid conditions

A clinical evaluation committee assessment of recombinant human tissue factor pathway inhibitor (tifacogin) in patients with severe community-acquired pneumonia

INTRODUCTION: The purpose of this analysis was to determine the potential efficacy of recombinant human tissue factor pathway inhibitor (tifacogin) in a subpopulation of patients with community-acquired pneumonia (CAP) from a phase III study of severe sepsis. METHODS : A retrospective review of patients with suspected pneumonia was conducted by an independent clinical evaluation committee (CEC) blinded to treatment assignment. The CEC reanalyzed data from patients enrolled in an international multicenter clinical trial of sepsis who had a diagnosis of pneumonia as the probable source of sepsis. The primary efficacy measure was all-cause 28-day mortality. RESULTS: Of 847 patients identified on case report forms with a clinical diagnosis of pneumonia, 780 (92%) were confirmed by the CEC to have pneumonia. Of confirmed pneumonia cases, 496 (63.6%) met the definition for CAP. In the CEC CAP population, the mortality rates of the tifacogin and placebo groups were 70/251 (27.9%) and 80/245 (32.7%), respectively. The strongest signals were seen in patients with CAP not receiving concomitant heparin, having microbiologically confirmed infection, or having the combination of documented infection and no heparin. The reduction in mortality in this narrowly defined subgroup when treated with tifacogin compared with placebo was statistically significant (17/58 [29.3%] with tifacogin and 28/54 [51.9%] with placebo; unadjusted P value of less than 0.02). CONCLUSIONS: Tifacogin administration did not significantly reduce mortality in any severe CAP patient. Exploratory analyses showed an improved survival in patients who did not receive concomitant heparin with microbiologically confirmed infections. These data support the rationale of an ongoing phase III study exploring the potential benefit of tifacogin in severe CAP. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00084071

Outcomes in participants with failure of initial antibacterial therapy for hospital-acquired/ventilator-associated bacterial pneumonia prior to enrollment in the randomized, controlled phase 3 ASPECT-NP trial of ceftolozane/tazobactam versus meropenem

BACKGROUND: Ceftolozane/tazobactam, a combination antibacterial agent comprising an anti-pseudomonal cephalosporin and β-lactamase inhibitor, is approved for the treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) in adults. Participants in the ASPECT-NP trial received ceftolozane/tazobactam (3 g [2 g ceftolozane/1 g tazobactam] every 8 h) or meropenem (1 g every 8 h). Participants failing prior antibacterial therapy for the current HABP/VABP episode at study entry had lower 28-day all-cause mortality (ACM) rates with ceftolozane/tazobactam versus meropenem treatment. Here, we report a post hoc analysis examining this result. METHODS: The phase 3, randomized, controlled, double-blind, multicenter, noninferiority trial compared ceftolozane/tazobactam versus meropenem for treatment of adults with ventilated HABP/VABP; eligibility included those failing prior antibacterial therapy for the current HABP/VABP episode at study entry. The primary and key secondary endpoints were 28-day ACM and clinical response at test of cure (TOC), respectively. Participants who were failing prior therapy were a prospectively defined subgroup; however, subgroup analyses were not designed for noninferiority testing. The 95% CIs for treatment differences were calculated as unstratified Newcombe CIs. Post hoc analyses were performed using multivariable logistic regression analysis to determine the impact of baseline characteristics and treatment on clinical outcomes in the subgroup who were failing prior antibacterial therapy. RESULTS: In the ASPECT-NP trial, 12.8% of participants (93/726; ceftolozane/tazobactam, n = 53; meropenem, n = 40) were failing prior antibacterial therapy at study entry. In this subgroup, 28-day ACM was higher in participants who received meropenem versus ceftolozane/tazobactam (18/40 [45.0%] vs 12/53 [22.6%]; percentage difference [95% CI]: 22.4% [3.1 to 40.1]). Rates of clinical response at TOC were 26/53 [49.1%] for ceftolozane/tazobactam versus 15/40 [37.5%] for meropenem (percentage difference [95% CI]: 11.6% [- 8.6 to 30.2]). Multivariable regression analysis determined concomitant vasopressor use and treatment with meropenem were significant factors associated with risk of 28-day ACM. Adjusting for vasopressor use, the risk of dying after treatment with ceftolozane/tazobactam was approximately one-fourth the risk of dying after treatment with meropenem. CONCLUSIONS: This post hoc analysis further supports the previously demonstrated lower ACM rate for ceftolozane/tazobactam versus meropenem among participants who were failing prior therapy, despite the lack of significant differences in clinical cure rates. CLINICALTRIALS: gov registration NCT02070757 . Registered February 25, 2014, clinicaltrials.gov/ct2/show/NCT02070757

Outcomes in participants with ventilated nosocomial pneumonia and organ failure treated with ceftolozane/tazobactam versus meropenem: A subset analysis of the phase 3, randomized, controlled ASPECT-NP trial

BACKGROUND: The pivotal ASPECT-NP trial showed ceftolozane/tazobactam was non-inferior to meropenem for the treatment of ventilated hospital-acquired/ventilator-associated bacterial pneumonia (vHABP/VABP). Here, we evaluated treatment outcomes by degree of respiratory or cardiovascular dysfunction. METHODS: This was a subset analysis of data from ASPECT-NP, a randomized, double-blind, non-inferiority trial (ClinicalTrials.gov NCT02070757). Adults with vHABP/VABP were randomized 1:1 to 3 g ceftolozane/tazobactam or 1 g meropenem every 8 h for 8-14 days. Outcomes in participants with a baseline respiratory component of the Sequential Organ Failure Assessment (SOFA) score (R-SOFA) ≥ 2 (indicative of severe respiratory failure), cardiovascular component of the SOFA score (CV-SOFA) ≥ 2 (indicative of shock), or R-SOFA ≥ 2 plus CV-SOFA ≥ 2 were compared by treatment arm. The efficacy endpoint of primary interest was 28-day all-cause mortality. Clinical response, time to death, and microbiologic response were also evaluated. RESULTS: There were 726 participants in the intention-to-treat population; 633 with R-SOFA ≥ 2 (312 ceftolozane/tazobactam, 321 meropenem), 183 with CV-SOFA ≥ 2 (84 ceftolozane/tazobactam, 99 meropenem), and 160 with R-SOFA ≥ 2 plus CV-SOFA ≥ 2 (69 ceftolozane/tazobactam, 91 meropenem). Baseline characteristics, including causative pathogens, were generally similar in participants with R-SOFA ≥ 2 or CV-SOFA ≥ 2 across treatment arms. The 28-day all-cause mortality rate was 23.7% and 24.0% [difference: 0.3%, 95% confidence interval (CI) - 6.4, 6.9] for R-SOFA ≥ 2, 33.3% and 30.3% (difference: - 3.0%, 95% CI - 16.4, 10.3) for CV-SOFA ≥ 2, and 34.8% and 30.8% (difference: - 4.0%, 95% CI - 18.6, 10.3), respectively, for R-SOFA ≥ 2 plus CV-SOFA ≥ 2. Clinical cure rates were as follows: 55.8% and 54.2% (difference: 1.6%, 95% CI - 6.2, 9.3) for R-SOFA ≥ 2, 53.6% and 55.6% (difference: - 2.0%, 95% CI - 16.1, 12.2) for CV-SOFA ≥ 2, and 53.6% and 56.0% (difference: - 2.4%, 95% CI - 17.6, 12.8), respectively, for R-SOFA ≥ 2 plus CV-SOFA ≥ 2. Time to death was comparable in all SOFA groups across both treatment arms. A higher rate of microbiologic eradication/presumed eradication was observed for CV-SOFA ≥ 2 and R-SOFA ≥ 2 plus CV-SOFA ≥ 2 with ceftolozane/tazobactam compared to meropenem. CONCLUSIONS: The presence of severe respiratory failure or shock did not affect the relative efficacy of ceftolozane/tazobactam versus meropenem; either agent may be used to treat critically ill patients with vHABP/VABP. TRIAL REGISTRATION: ClinicalTrials.gov NCT02070757. Registered 25 February 2014, https://clinicaltrials.gov/ct2/show/NCT02070757

Ceftolozane/tazobactam versus meropenem in patients with ventilated hospital-acquired bacterial pneumonia: Subset analysis of the ASPECT-NP randomized, controlled phase 3 trial

BACKGROUND: Ceftolozane/tazobactam is approved for treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) at double the dose approved for other infection sites. Among nosocomial pneumonia subtypes, ventilated HABP (vHABP) is associated with the lowest survival. In the ASPECT-NP randomized, controlled trial, participants with vHABP treated with ceftolozane/tazobactam had lower 28-day all-cause mortality (ACM) than those receiving meropenem. We conducted a series of post hoc analyses to explore the clinical significance of this finding. METHODS: ASPECT-NP was a multinational, phase 3, noninferiority trial comparing ceftolozane/tazobactam with meropenem for treating vHABP and VABP; study design, efficacy, and safety results have been reported previously. The primary endpoint was 28-day ACM. The key secondary endpoint was clinical response at test-of-cure. Participants with vHABP were a prospectively defined subgroup, but subgroup analyses were not powered for noninferiority testing. We compared baseline and treatment factors, efficacy, and safety between ceftolozane/tazobactam and meropenem in participants with vHABP. We also conducted a retrospective multivariable logistic regression analysis in this subgroup to determine the impact of treatment arm on mortality when adjusted for significant prognostic factors. RESULTS: Overall, 99 participants in the ceftolozane/tazobactam and 108 in the meropenem arm had vHABP. 28-day ACM was 24.2% and 37.0%, respectively, in the intention-to-treat population (95% confidence interval [CI] for difference: 0.2, 24.8) and 18.2% and 36.6%, respectively, in the microbiologic intention-to-treat population (95% CI 2.5, 32.5). Clinical cure rates in the intention-to-treat population were 50.5% and 44.4%, respectively (95% CI - 7.4, 19.3). Baseline clinical, baseline microbiologic, and treatment factors were comparable between treatment arms. Multivariable regression identified concomitant vasopressor use and baseline bacteremia as significantly impacting ACM in ASPECT-NP; adjusting for these two factors, the odds of dying by day 28 were 2.3-fold greater when participants received meropenem instead of ceftolozane/tazobactam. CONCLUSIONS: There were no underlying differences between treatment arms expected to have biased the observed survival advantage with ceftolozane/tazobactam in the vHABP subgroup. After adjusting for clinically relevant factors found to impact ACM significantly in this trial, the mortality risk in participants with vHABP was over twice as high when treated with meropenem compared with ceftolozane/tazobactam. TRIAL REGISTRATION: clinicaltrials.gov, NCT02070757. Registered 25 February, 2014, clinicaltrials.gov/ct2/show/NCT02070757