Genetic Regulation of Cytokine Response in Patients with Acute Community-Acquired Pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) is an acute disease condition with a high risk of rapid deteriorations. We analysed the influence of genetics on cytokine regulation to obtain a better understanding of patient's heterogeneity. METHODS: For up to N = 389 genotyped participants of the PROGRESS study of hospitalised CAP patients, we performed a genome-wide association study of ten cytokines IL-1ß, IL-6, IL-8, IL-10, IL-12, MCP-1 (MCAF), MIP-1α (CCL3), VEGF, VCAM-1, and ICAM-1. Consecutive secondary analyses were performed to identify independent hits and corresponding causal variants. RESULTS: 102 SNPs from 14 loci showed genome-wide significant associations with five of the cytokines. The most interesting associations were found at 6p21.1 for VEGF (p = 1.58 × 10-20), at 17q21.32 (p = 1.51 × 10-9) and at 10p12.1 (p = 2.76 × 10-9) for IL-1ß, at 10p13 for MIP-1α (CCL3) (p = 2.28 × 10-9), and at 9q34.12 for IL-10 (p = 4.52 × 10-8). Functionally plausible genes could be assigned to the majority of loci including genes involved in cytokine secretion, granulocyte function, and cilial kinetics. CONCLUSION: This is the first context-specific genetic association study of blood cytokine concentrations in CAP patients revealing numerous biologically plausible candidate genes. Two of the loci were also associated with atherosclerosis with probable common or consecutive pathomechanisms.

Associations of Serum Resistin With the Severity and Prognosis in Patients With Community-Acquired Pneumonia.

Background: Resistin is an endogenous ligand of Toll-like receptor 4 that activates several inflammatory signals. But the physiological function of resistin in community-acquired pneumonia (CAP) remains unknown. The goal of this research was to explore the associations between serum resistin and the severity and prognosis in CAP patients through a retrospective cohort study. Methods: All 212 CAP patients and 106 healthy cases were enrolled. Demographic characteristics were extracted. Serum resistin was determined via enzyme-linked immunosorbent assay. The prognosis was tracked in CAP patients. Results: Serum resistin on admission was raised in CAP patients compared with control cases. The level of resistin was gradually increased in parallel with CAP severity scores in CAP patients. Pearson and Spearman analyses revealed that serum resistin was positively correlated with CAP severity scores, white blood cells, urea nitrogen, creatinine, and inflammatory cytokines among CAP patients. There were negative relationships between resistin and hematocrit and albumin in CAP patients. Besides, linear and logistic regression analyses further indicated that serum resistin on admission was positively associated with CAP severity scores among CAP patients. Follow-up research revealed that serum resistin elevation on admission prolonged hospital stay in CAP patients. Conclusion: Serum resistin on admission is positively correlated with the severity and hospital stay in CAP patients, indicating that resistin may be involved in the physiological process of CAP. Serum resistin may be a potential biomarker in the diagnosis and prognosis for CAP.

Metabolomic profiling of microbial disease etiology in community-acquired pneumonia.

Diagnosis of microbial disease etiology in community-acquired pneumonia (CAP) remains challenging. We undertook a large-scale metabolomics study of serum samples in hospitalized CAP patients to determine if host-response associated metabolites can enable diagnosis of microbial etiology, with a specific focus on discrimination between the major CAP pathogen groups S. pneumoniae, atypical bacteria, and respiratory viruses. Targeted metabolomic profiling of serum samples was performed for three groups of hospitalized CAP patients with confirmed microbial etiologies: S. pneumoniae (n = 48), atypical bacteria (n = 47), or viral infections (n = 30). A wide range of 347 metabolites was targeted, including amines, acylcarnitines, organic acids, and lipids. Single discriminating metabolites were selected using Student's T-test and their predictive performance was analyzed using logistic regression. Elastic net regression models were employed to discover metabolite signatures with predictive value for discrimination between pathogen groups. Metabolites to discriminate S. pneumoniae or viral pathogens from the other groups showed poor predictive capability, whereas discrimination of atypical pathogens from the other groups was found to be possible. Classification of atypical pathogens using elastic net regression models was associated with a predictive performance of 61% sensitivity, 86% specificity, and an AUC of 0.81. Targeted profiling of the host metabolic response revealed metabolites that can support diagnosis of microbial etiology in CAP patients with atypical bacterial pathogens compared to patients with S. pneumoniae or viral infections.

Lipid profiles and differential lipids in serum related to severity of community-acquired pneumonia: A pilot study.

This study aimed to characterize the lipidomic responses to community-acquired pneumonia (CAP) and provide new insight into the underlying mechanisms of pathogenesis and potential avenues for diagnostic and therapeutic treatments. This study was performed from January 2017 to October 2018. Lipidomic profiles were generated using ultra high-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) platform. Spearman's rank correlation test and multiple linear regression analysis were applied to explore the correlation between changes in the relative abundance of lipids and clinical parameters. Kaplan-Meier methods were used to build 30-day survival curves. From the UHPLC-MS/MS results, a total of 509 and 195 lipid species were detected in the positive and negative ionization mode respectively. Positive ionization covered six lipid classes (glycerol-phospholipids, glycerolipids, sphingolipids, sterol-lipids, prenol-lipids, and fatty acid), whilst negative ionization covered three (glycerol-phospholipids, sphingolipids, fatty acid). Four lipids were selected as targets: PC (16:0_18:1), PC (18:2_20:4), PC (36:4), and PC (38:6). The relative increase of the areas under the curves for all four lipids were superior to the pneumonia severity index and CURB-65 (confusion, urea, respiratory rate, blood pressure, and age ≥65 years old) for discriminating severe CAP from CAP. Decreasing relative levels of PC (18:2_20:4), PC (38:6), and PC (36:4) were negatively related to fraction of inspiration O2; Changes in the relative abundance of PC (16:0_18:1) and PC (18:2_20:4) had significantly linear relationship with procalcitonin. Patients with an elevated level of PC (16:0_18:1) had significantly longer duration of hospital stays. As the relative abundance of PC (18:2_20:4), PC (36:4), and PC (38:6) decreased, the length of hospitalization days and 30-day mortality rate increased significantly (all log-rank p<0.05). Therefore, using the UHPLC-MS/MS platform's serum lipidomic approach can help reveal changes in lipid abundance during CAP and establish lipid profiles related to disease severity.

Noninvasive ventilation and high-flow oxygen therapy for severe community-acquired pneumonia.

PURPOSE OF REVIEW: We review the evidence on the use of noninvasive respiratory supports (noninvasive ventilation and high-flow nasal cannula oxygen therapy) in patients with acute respiratory failure because of severe community-acquired pneumonia. RECENT FINDINGS: Noninvasive ventilation is strongly advised for the treatment of hypercapnic respiratory failure and recent evidence justifies its use in patients with hypoxemic respiratory failure when delivered by helmet. Indeed, such interface allows alveolar recruitment by providing high level of positive end-expiratory pressure, which improves hypoxemia. On the other hand, high-flow nasal cannula oxygen therapy is effective in patients with hypoxemic respiratory failure and some articles support its use in patients with hypercapnia. However, early identification of noninvasive respiratory supports treatment failure is crucial to prevent delayed orotracheal intubation and protective invasive mechanical ventilation. SUMMARY: Noninvasive ventilation is the first-line therapy in patients with acute hypercapnic respiratory failure because of pneumonia. Although an increasing amount of evidence investigated the application of noninvasive respiratory support to hypoxemic respiratory failure, the optimal ventilatory strategy in this setting is uncertain. Noninvasive mechanical ventilation delivered by helmet and high-flow nasal cannula oxygen therapy appear as promising tools but their role needs to be confirmed by future research.

Characterization of the Inflammatory Response to Severe COVID-19 Illness.

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1ß, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1ß, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1ß, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.

Kidney injury induced by elevated histones in community-acquired pneumonia.

Previous studies showed that extracellular histones could damage organs, but the role of extracellular histones in pneumonia patients with acute kidney injury (AKI) is unknown. This study aims to investigate the impact of extracellular histones on patients with community-acquired pneumonia (CAP) developed AKI. Blood samples were obtained within 24 h after admission to hospital from patients who were diagnosed with CAP. According to the discharge diagnosis, the patients were divided into 2 groups (Non-AKI and AKI). In vitro, A549 cells were treated with lipopolysaccharides (LPS) and conditioned media were collected. HK2 cells were exposed to the conditioned media or not. Cells proliferation and apoptosis of HK2 were determined. Clinically, Log2 Histones (OR 3.068; 95% CI 1.544-6.097, P = 0.001) and estimated glomerular filtration rate (eGFR) (OR 0.945; 95% CI 0.914-0.978, P = 0.001) were predictors of AKI in CAP patients. Compared to the lower histones group, patients in the higher histones group were more likely to be admitted to ICU, receive mechanical ventilation, and have a longer length of in-hospital stay. In vitro, A549 cells injured by LPS released extracellular histones, in conditioned media which significantly promoted HK2 cells apoptosis. Extracellular histones was a high risk factor for developing AKI in CAP patients and a predictor of worse short-term outcomes. We also showed that extracellular histones in conditioned media damaged HK2 cells.Trial registration number: KY20181102-03; Date of registration: 20181102.

Patients with Community Acquired Pneumonia Exhibit Depleted Vitamin C Status and Elevated Oxidative Stress.

Pneumonia is a severe lower respiratory tract infection that is a common complication and a major cause of mortality of the vitamin C-deficiency disease scurvy. This suggests an important link between vitamin C status and lower respiratory tract infections. Due to the paucity of information on the vitamin C status of patients with pneumonia, we assessed the vitamin C status of 50 patients with community-acquired pneumonia and compared these with 50 healthy community controls. The pneumonia cohort comprised 44 patients recruited through the Acute Medical Assessment Unit (AMAU) and 6 patients recruited through the Intensive Care Unit (ICU); mean age 68 ± 17 years, 54% male. Clinical, microbiological and hematological parameters were recorded. Blood samples were tested for vitamin C status using HPLC with electrochemical detection and protein carbonyl concentrations, an established marker of oxidative stress, using ELISA. Patients with pneumonia had depleted vitamin C status compared with healthy controls (23 ± 14 µmol/L vs. 56 ± 24 µmol/L, p < 0.001). The more severe patients in the ICU had significantly lower vitamin C status than those recruited through AMAU (11 ± 3 µmol/L vs. 24 ± 14 µmol/L, p = 0.02). The pneumonia cohort comprised 62% with hypovitaminosis C and 22% with deficiency, compared with only 8% hypovitaminosis C and no cases of deficiency in the healthy controls. The pneumonia cohort also exhibited significantly elevated protein carbonyl concentrations compared with the healthy controls (p < 0.001), indicating enhanced oxidative stress in the patients. We were able to collect subsequent samples from 28% of the cohort (mean 2.7 ± 1.7 days; range 1-7 days). These showed no significant differences in vitamin C status or protein carbonyl concentrations compared with baseline values (p = 0.6). Overall, the depleted vitamin C status and elevated oxidative stress observed in the patients with pneumonia indicates an enhanced requirement for the vitamin during their illness. Therefore, these patients would likely benefit from additional vitamin C supplementation to restore their blood and tissue levels to optimal. This may decrease excessive oxidative stress and aid in their recovery.

Formyl-Peptide Receptor Activation Enhances Phagocytosis of Community-Acquired Methicillin-Resistant Staphylococcus aureus.

BACKGROUND: Formyl-peptide receptors (FPRs) are important pattern recognition receptors that sense specific bacterial peptides. Formyl-peptide receptors are highly expressed on neutrophils and monocytes, and their activation promotes the migration of phagocytes to sites of infection. It is currently unknown whether FPRs may also influence subsequent processes such as bacterial phagocytosis and killing. Staphylococcus aureus, especially highly pathogenic community-acquired methicillin-resistant S aureus strains, release high amounts of FPR2 ligands, the phenol-soluble modulins. METHODS: We demonstrate that FPR activation leads to upregulation of complement receptors 1 and 3 as well as FCγ receptor I on neutrophils and, consequently, increased opsonic phagocytosis of S aureus and other pathogens. RESULTS: Increased phagocytosis promotes killing of S aureus and interleukin-8 release by neutrophils. CONCLUSIONS: We show here for the first time that FPRs govern opsonic phagocytosis. Manipulation of FPR2 activation could open new therapeutic opportunities against bacterial pathogens.

Methicillin-Resistant Staphylococcus aureus Infection and Treatment Options.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of infection worldwide, including a wide array of both hospital- and community-acquired infections-most commonly bacteremia, upper and lower respiratory tract infection, skin and soft-tissue infection, osteomyelitis, and septic arthritis. This chapter describes the epidemiology of MRSA infection, its ability to confer antibiotic resistance and produce a wide array of virulence factors, and its pivotal role in human infection, especially cystic fibrosis. It also provides an introduction to the strategies for treatment of both chronic and acute MRSA infections.

New insights into pediatric community-acquired pneumonia gained from untargeted metabolomics: A preliminary study.

BACKGROUND: Available diagnostics often fail to distinguish viral from bacterial causes of pediatric community-acquired pneumonia (pCAP). Metabolomics, which aims at characterizing diseases based on their metabolic signatures, has been applied to expand pathophysiological understanding of many diseases. In this exploratory study, we used the untargeted metabolomic analysis to shed new light on the etiology of pCAP. METHODS: Liquid chromatography coupled with mass spectrometry was used to quantify the metabolite content of urine samples collected from children hospitalized for CAP of pneumococcal or viral etiology, ascertained using a conservative algorithm combining microbiological and biochemical data. RESULTS: Fifty-nine children with CAP were enrolled over 16 months. Pneumococcal and viral cases were distinguished by means of a multivariate model based on 93 metabolites, 20 of which were identified and considered as putative biomarkers. Among these, six metabolites belonged to the adrenal steroid synthesis and degradation pathway. CONCLUSIONS: This preliminary study suggests that viral and pneumococcal pneumonia differently affect the systemic metabolome, with a stronger disruption of the adrenal steroid pathway in pneumococcal pneumonia. This finding may lead to the discovery of novel diagnostic biomarkers and bring us closer to personalized therapy for pCAP.

The Glycemic Gap and 90-Day Mortality in Community-acquired Pneumonia. A Prospective Cohort Study.

Rationale: Hyperglycemia is associated with mortality in patients with community-acquired pneumonia (CAP), and hyperglycemia may be a biomarker of severity. However, hyperglycemia has a major disadvantage because the association is diminished in patients with diabetes mellitus (DM). This hampers the use of hyperglycemia as a biomarker. Accounting for habitual glucose levels could overcome this disadvantage.Objectives: We hypothesized that the glycemic gap (the difference between plasma glucose and the estimated average glucose) may be associated with mortality irrespective of DM.Methods: Among 1,933 adults with CAP included in a prospective multicenter cohort, we investigated the association between the glycemic gap and 90-day mortality. Hemoglobin A1c was used to estimate the average glucose. The association was assessed with Cox proportional hazard models after adjustment for age, sex, CURB-65 (Confusion, urea >7 mmol/L, respiratory rate ≥30 breaths/minute, systolic blood pressure <90 mmHg or diastolic blood pressure ≤60 mmHg and age ≥65 years), and comorbidities. In the prespecified analysis the absolute and relative glycemic gaps were used as a continuous variable. In a post hoc analysis, the absolute and relative glycemic gaps were used as a categorical variable grouped according to quartiles.Results: In the post hoc analysis, patients with the lowest (negative) and highest (positive) absolute glycemic gap quartiles had increased risk of 90-day mortality (hazard ratio, 2.6; 95% confidence interval, 1.02-6.65; and hazard ratio, 2.5; 95% confidence interval, 1.01-6.06, respectively). A similar association was found for the relative glycemic gap. The associations were independent of age, CURB-65 score, sex, or number of comorbidities and not modified by DM.Conclusions: Patients with the highest and lowest glycemic gap may have an increased risk of 90-day mortality, and the association was not modified by DM. These associations were found in an exploratory post hoc analysis and should be validated in other populations before further conclusions can be made.

Hyponatremia in infants with community-acquired infections on hospital admission.

Acute moderate to severe gastroenteritis is traditionally associated with hypernatremia but recent observations suggest that hypernatremia is currently less common than hyponatremia. The latter has sometimes been documented also in children with acute community-acquired diseases, such as bronchiolitis and pyelonephritis. We investigated the prevalence of dysnatremia in children with acute moderate severe gastroenteritis, bronchiolitis and pyelonephritis. This prospective observational study included 400 consecutive previously healthy infants ≥4 weeks to ≤24 months of age (232 males and 168 females): 160 with gastroenteritis and relevant dehydration, 160 with moderate-severe bronchiolitis and 80 with pyelonephritis admitted to our emergency department between 2009 and 2017. Circulating sodium was determined by means of direct potentiometry. For analysis, the Kruskal-Wallis test and the Fisher's exact test were used. Hyponatremia was found in 214 of the 400 patients. It was common in gastroenteritis (43%) and significantly more frequent in bronchiolitis (57%) and pyelonephritis (68%). Patients with hyponatremia were significantly younger than those without hyponatremia (3.9 [1.6-13] versus 7.5 [3.4-14] months). The gender ratio was similar in children with and without hyponatremia. Hyponatremia was associated with further metabolic abnormalities (hypokalemia, hyperkalemia, metabolic acidosis or metabolic alkalosis) in gastroenteritis (71%) and pyelonephritis (54%), and always isolated in bronchiolitis. In conclusion, hyponatremia is common at presentation among previously healthy infants with gastroenteritis, bronchiolitis or pyelonephritis. These data have relevant consequences for the nutrition and rehydration management in these conditions.

Biomarkers of Community-Acquired Pneumonia: A Key to Disease Diagnosis and Management.

Community-acquired pneumonia (CAP) is a dangerous disease caused by a spectrum of bacterial and viral pathogens. The choice of specific therapy and the need for hospitalization or transfer to the intensive care unit are determined by the causative agent and disease severity. The microbiological analysis of sputum largely depends on the quality of the material obtained. The prediction of severity and the duration of therapy are determined individually, and existing prognostic scales are used generally. This review examines the possibilities of using specific serological biomarkers to detect the bacterial or viral aetiology of CAP and to assess disease severity. Particular emphasis is placed on the use of biomarker signatures and the discovery of biomarker candidates for a single multiplex analysis.

Inflammatory responses relate to distinct bronchoalveolar lavage lipidome in community-acquired pneumonia patients: a pilot study.

BACKGROUND: Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Antibiotics are losing their effectiveness due to the emerging infectious diseases, the scarcity of novel antibiotics, and the contributions of antibiotic misuse and overuse to resistance. Characterization of the lipidomic response to pneumonia and exploring the "lipidomic phenotype" can provide new insight into the underlying mechanisms of pathogenesis and potential avenues for diagnostic and therapeutic treatments. METHODS: Lipid profiles of bronchoalveolar lavage fluid (BALF) samples were generated through untargeted lipidomic profiling analysis using high-performance liquid chromatography with mass spectrometry (HPLC-MS). Principal component analysis (PCA) was applied to identify possible sources of variations among samples. Partitioning clustering analysis (k-means) was employed to evaluate the existence of distinct lipidomic clusters. RESULTS: PCA showed that BALF lipidomes differed significantly between CAP (n = 52) and controls (n = 68, including 35 healthy volunteers and 33 patients with non-infectious lung diseases); while no clear separation was found between severe CAP and non-severe CAP cases. Lactosylceramides were the most prominently elevated lipid constituent in CAP. Clustering analysis revealed three separate lipid profiles; subjects in each cluster exhibited significant differences in disease severity, incidence of hypoxemia, percentages of phagocytes in BALF, and serum concentrations of albumin and total cholesterol (all p < 0.05). In addition, SM (d34:1) was negatively related to macrophage (adjusted r = - 0.462, p < 0.0001) and PE (18:1p/20:4) was positively correlated with polymorphonuclear neutrophil (PMN) percentages of BALF (adjusted r = 0.541, p < 0.0001). The 30-day mortality did not differ amongst three clusters (p < 0.05). CONCLUSIONS: Our data suggest that specific lower airway lipid composition is related to different intensities of host inflammatory responses, and may contribute to functionally relevant shifts in disease pathogenesis in CAP individuals. These findings argue for the need to tailor therapy based on specific lipid profiles and related inflammatory status. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03093220). Registered on 28 March 2017 (retrospectively registered).

Population Pharmacokinetic Modeling and Probability of Target Attainment Analyses in Asian Patients With Community-Acquired Pneumonia Treated With Ceftaroline Fosamil.

Efficacy of ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, was demonstrated in a phase 3 study of hospitalized Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III-IV community-acquired pneumonia (NCT01371838). The objectives of the current analysis were to expand an existing ceftaroline and ceftaroline fosamil population pharmacokinetic (PK) model with data from this phase 3 study and a phase 1 study (NCT01458743) assessing ceftaroline PK in healthy Chinese volunteers and to evaluate the probability of PK/pharmacodynamic (PK/PD) target attainment (PTA) in Asian patients with community-acquired pneumonia (CAP) treated with ceftaroline fosamil. The ceftaroline plasma concentration-time course was simulated for 5000 Asian patients with CAP for different renal function subgroups using the final model. PTA was calculated for Streptococcus pneumoniae, Staphylococcus aureus, and non-extended-spectrum ß-lactamase-producing Enterobacteriaceae. PTA was also evaluated for ceftaroline MIC90 values of isolates collected from Asia-Pacific surveillance studies (2012-2014) and for EUCAST and FDA/CLSI ceftaroline susceptibility break points. The final model reasonably described the ceftaroline PK. Race was not found to be a significant covariate impacting ceftaroline PK, suggesting similar ceftaroline PK in Asian and Western populations when corrected for body weight. High PTAs (90%-100%) were predicted for Asian patients with CAP treated with ceftaroline fosamil, covering MIC90 values of target CAP pathogens from the region. Similarly, >90% PTAs were predicted at EUCAST and FDA/CLSI clinical break points for these pathogens. These results support the use of the ceftaroline fosamil dosing regimens approved in Europe and the United States in Asian patients with PORT III-IV CAP.

Omadacycline: A New Tetracycline Antibiotic.

OBJECTIVE: To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosage, and administration of omadacycline, a new tetracycline antibiotic. DATA SOURCES: A literature search through PubMed, Google Scholar, and clinicaltrials.gov was conducted (2008 to October 2018) using the search terms omadacycline and PTK-0796. Abstracts presented at recent conferences, prescribing information and information from the FDA and the manufacturer's website were reviewed. STUDY SELECTION AND DATA EXTRACTION: Preclinical data and published phase 1, 2, and 3 studies were evaluated. DATA SYNTHESIS: Omadacycline displays in vitro activity against a wide range of bacteria. Clinical trials have shown that omadacycline is noninferior to linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and noninferior to moxifloxacin for the treatment of community-acquired bacterial pneumonia (CABP). A loading dose of 200 mg intravenously (IV) once or 100 mg IV twice or 450 mg orally once is recommended followed by a maintenance dose of 100 mg IV or 300 mg orally once daily. No dosage adjustment is needed in patients with renal or hepatic impairment. Omadacycline is well tolerated, with nausea being a common adverse effect, but is associated with food and drug interactions. Relevance to Patient Care and Clinical Practice: Omadacycline is active against staphylococci, including methicillin-resistant strains, and streptococci, including tetracycline-resistant strains, as well as atypical bacteria. Omadacycline provides clinicians with an additional parenteral and oral option for the treatment of adults with ABSSSI and CABP. CONCLUSION: Omadacycline is an alternative treatment option for ABSSSI and CABP.

Fibroblast growth factor 21 predicts outcome in community-acquired pneumonia: secondary analysis of two randomised controlled trials.

Acute systemic inflammatory conditions are accompanied by profound alterations of metabolism. However, the role of fibroblast growth factor 21 (FGF21), a recently identified central regulator of metabolism, is largely unknown in community-acquired pneumonia (CAP). This study aims to characterise the pattern of FGF21 in pneumonia and associations with disease severity and outcome.This is a secondary analysis of two independent multicentre randomised controlled trials in patients presenting to the emergency department with CAP. Primary and secondary efficacy parameters included 30-day mortality, length of hospital stay, time to clinical stability and duration of antibiotic treatment.A total of 509 patients were included in the analysis. FGF21 levels at admission strongly correlated with disease severity, as measured by the Pneumonia Severity Index. Increased levels of FGF21 were associated with prolonged time to clinical stability, antibiotic treatment and hospitalisation. FGF21 levels at admission were significantly higher in nonsurvivors than in survivors, yielding a 1.61-fold increased adjusted odds ratio of 30-day mortality (95% CI 1.21-2.14; p=0.001). Moreover, FGF21 was found to identify patients for 30-day mortality with superior discriminative power compared with routine diagnostic markers.Moderate-to-severe CAP patients with higher levels of FGF21 were at increased risk for clinical instability, prolonged hospitalisation and 30-day all-cause mortality.

Serum High-Sensitivity C Reactive Protein Improves Sensitivity of CURB-65 in Predicting ICU Admission and Mortality in Community-Acquired Pneumonia Patients.

BACKGROUND: The CURB-65 scoring system is a simple tool in assessment and prognosis prediction for communityacquired pneumonia (CAP) patients. However, the variations in performance of CURB-65 in young and elderly patients, underestimation or overestimation of the severity, and mortality have often been reported. The aim of this study was to investigate the usefulness of serum high-sensitivity C reactive protein (hs-CRP) combined with CURB-65 in predicting ICU admission and 30-day mortality in CAP patients. METHODS: We conducted a retrospective study. All patients over 18 years of age with a primary diagnosis of CAP were included, all of them received serum hs-CRP test and CURB-65 scaring evaluation. The main outcome measures were ICU admission and 30-day mortality. Receiver operating characteristic curves (ROC) were used to evaluate the sensitivity and specificity of the CURB-65 model and hs-CRP combined CURB-65 augmented model in predicting the main outcomes. RESULTS: Data from 150 patients was analyzed, in which the rate for patients requiring ICU admission was 30.67%, and the ultimate mortality rate was 24%. The areas of ROC curves (AUC) of CURB-65 was 0.859 (95% CI 0.705 to 1.000), hs-CRP combined CURB-65 augmented model was 0.864 (95% CI 0.692 to 1.000), ROC curve analyses showed the augmented model had higher sensitivity than the CURB-65 model in predicting main outcomes (p = 0.001). CONCLUSIONS: Measurement of serum hs-CRP in addition to the CURB-65 model improved the clinical usefulness in predicting ICU admission and mortality in CAP patients.