Resistance mechanisms and molecular epidemiology of Pseudomonas aeruginosa strains from patients with bronchiectasis.

BACKGROUND: Non-cystic fibrosis bronchiectasis (BE) is a chronic structural lung condition that facilitates chronic colonization by different microorganisms and courses with recurrent respiratory infections and frequent exacerbations. One of the main pathogens involved in BE is Pseudomonas aeruginosa. OBJECTIVES: To determine the molecular mechanisms of resistance and the molecular epidemiology of P. aeruginosa strains isolated from patients with BE. METHODS: A total of 43 strains of P. aeruginosa were isolated from the sputum of BE patients. Susceptibility to the following antimicrobials was analysed: ciprofloxacin, meropenem, imipenem, amikacin, tobramycin, aztreonam, piperacillin/tazobactam, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, cefepime and colistin. The resistance mechanisms present in each strain were assessed by PCR, sequencing and quantitative RT-PCR. Molecular epidemiology was determined by MLST. Phylogenetic analysis was carried out using the eBURST algorithm. RESULTS: High levels of resistance to ciprofloxacin (44.19%) were found. Mutations in the gyrA, gyrB, parC and parE genes were detected in ciprofloxacin-resistant P. aeruginosa strains. The number of mutated QRDR genes was related to increased MIC. Different ß-lactamases were detected: blaOXA50, blaGES-2, blaIMI-2 and blaGIM-1. The aac(3)-Ia, aac(3)-Ic, aac(6″)-Ib and ant(2″)-Ia genes were associated with aminoglycoside-resistant strains. The gene expression analysis showed overproduction of the MexAB-OprM efflux system (46.5%) over the other efflux system. The most frequently detected clones were ST619, ST676, ST532 and ST109. CONCLUSIONS: Resistance to first-line antimicrobials recommended in BE guidelines could threaten the treatment of BE and the eradication of P. aeruginosa, contributing to chronic infection.

Short-Term Effects of Appropriate Empirical Antimicrobial Treatment with Ceftolozane/Tazobactam in a Swine Model of Nosocomial Pneumonia.

The rising frequency of multidrug-resistant and extensively drug-resistant (MDR/XDR) pathogens is making more frequent the inappropriate empirical antimicrobial therapy (IEAT) in nosocomial pneumonia, which is associated with increased mortality. We aim to determine the short-term benefits of appropriate empirical antimicrobial treatment (AEAT) with ceftolozane/tazobactam (C/T) compared with IEAT with piperacillin/tazobactam (TZP) in MDR Pseudomonas aeruginosa pneumonia. Twenty-one pigs with pneumonia caused by an XDR P. aeruginosa strain (susceptible to C/T but resistant to TZP) were ventilated for up to 72 h. Twenty-four hours after bacterial challenge, animals were randomized to receive 2-day treatment with either intravenous saline (untreated) or 25 to 50 mg of C/T per kg body weight (AEAT) or 200 to 225 mg of TZP per kg (IEAT) every 8 h. The primary outcome was the P. aeruginosa burden in lung tissue and the histopathology injury. P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage (BAL) fluid, the development of antibiotic resistance, and inflammatory markers were secondary outcomes. Overall, P. aeruginosa lung burden was 5.30 (range, 4.00 to 6.30), 4.04 (3.64 to 4.51), and 4.04 (3.05 to 4.88) log10CFU/g in the untreated, AEAT, and IEAT groups, respectively (P = 0.299), without histopathological differences (P = 0.556). In contrast, in tracheal secretions (P < 0.001) and BAL fluid (P = 0.002), bactericidal efficacy was higher in the AEAT group. An increased MIC to TZP was found in 3 animals, while resistance to C/T did not develop. Interleukin-1ß (IL-1ß) was significantly downregulated by AEAT in comparison to other groups (P = 0.031). In a mechanically ventilated swine model of XDR P. aeruginosa pneumonia, appropriate initial treatment with C/T decreased respiratory secretions' bacterial burden, prevented development of resistance, achieved the pharmacodynamic target, and may have reduced systemic inflammation. However, after only 2 days of treatment, P. aeruginosa tissue concentrations were moderately affected.

Pseudomonas aeruginosa in Bronchiectasis.

Pseudomonas aeruginosa (PA) in patients with bronchiectasis (BE) is associated with a poor outcome and quality of life, and its presence is considered a marker of disease severity. This opportunistic pathogen is known for its ability to produce biofilms on biotic or abiotic surfaces and to survive environmental stress exerted by antimicrobials, inflammation, and nutrient or oxygen depletion. The presence of PA biofilms has been linked to chronic respiratory infection in cystic fibrosis but not in BE. There is considerable inconsistency in the reported infection/eradication rates of PA and chronic PA. In addition, inadequate antimicrobial treatment may potentiate the progression from intermittent to chronic infection and also the emergence of antibiotic resistance. A better comprehension of the pathophysiology of PA infections and its implications for BE is urgently needed. This can drive improvements in diagnostic accuracy, can move us toward a new consensus definition of chronic infection, can better define the follow-up of patients at risk of PA, and can achieve more successful eradication rates. In addition, the new technological advances regarding molecular diagnostics, -omics, and biomarkers require us to reconsider our traditional concepts.

Association between physical activity and risk of hospitalisation in bronchiectasis.

BACKGROUND: Patients with bronchiectasis have a less active lifestyle than healthy peers, but the association with hospital admission has not been explored. The aim of this study was to investigate the association between 1) any physical activity variable; and 2) sedentary time, with hospitalisation due to exacerbation in adults with bronchiectasis. METHODS: In this prospective observational study, baseline lung function, quality of life, exercise tolerance, severity of bronchiectasis and physical activity were recorded. Physical activity was objectively assessed over a week using a SenseWear armband and the results were expressed in steps·day-1 and sedentary time. Number of hospitalisations due to a bronchiectasis exacerbation and time to first event were recorded after 1-year follow-up. RESULTS: Sixty-four patients with bronchiectasis were analysed, of whom 15 (23%) were hospitalised during the follow-up. Hospitalised patients showed poor baseline clinical and severity outcomes, fewer steps walked per day and more sedentary behaviour than the non-hospitalised group. Patients who walked ≤6290 steps·day-1 or spent ≥7.8 h·day-1 in sedentary behaviour had an increased risk of hospital admission due to bronchiectasis exacerbation at 1-year follow-up. Specifically, ≥7.8 h·day-1 of sedentary behaviour was associated with a 5.9-fold higher risk of hospital admission in the following year. CONCLUSIONS: Low levels of physical activity and high sedentary time at baseline were associated with a higher risk of hospitalisation due to bronchiectasis exacerbation. If these findings are validated in future studies, it might be appropriate to include physical activity and sedentary behaviour as an item in severity scores.

Nebulized Amikacin and Fosfomycin for Severe Pseudomonas aeruginosa Pneumonia: An Experimental Study.

OBJECTIVES: Latest trials failed to confirm merits of nebulized amikacin for critically ill patients with nosocomial pneumonia. We studied various nebulized and IV antibiotic regimens in a porcine model of severe Pseudomonas aeruginosa pneumonia, resistant to amikacin, fosfomycin, and susceptible to meropenem. DESIGN: Prospective randomized animal study. SETTING: Animal Research, University of Barcelona, Spain. SUBJECTS: Thirty female pigs. INTERVENTIONS: The animals were randomized to receive nebulized saline solution (CONTROL); nebulized amikacin every 6 hours; nebulized fosfomycin every 6 hours; IV meropenem alone every 8 hours; nebulized amikacin and fosfomycin every 6 hours; amikacin and fosfomycin every 6 hours, with IV meropenem every 8 hours. Nebulization was performed through a vibrating mesh nebulizer. The primary outcome was lung tissue bacterial concentration. Secondary outcomes were tracheal secretions P. aeruginosa concentration, clinical variables, lung histology, and development of meropenem resistance. MEASUREMENTS AND MAIN RESULTS: We included five animals into each group. Lung P. aeruginosa burden varied among groups (p < 0.001). In particular, IV meropenem and amikacin and fosfomycin + IV meropenem groups presented lower P. aeruginosa concentrations versus amikacin and fosfomycin, amikacin, CONTROL, and fosfomycin groups (p < 0.05), without significant difference between these two groups undergoing IV meropenem treatment. The sole use of nebulized antibiotics resulted in dense P. aeruginosa accumulation at the edges of the interlobular septa. Amikacin, amikacin and fosfomycin, and amikacin and fosfomycin + IV meropenem effectively reduced P. aeruginosa in tracheal secretions (p < 0.001). Pathognomonic clinical variables of respiratory infection did not differ among groups. Resistance to meropenem increased in IV meropenem group versus amikacin and fosfomycin + meropenem (p = 0.004). CONCLUSIONS: Our findings corroborate that amikacin and fosfomycin alone efficiently reduced P. aeruginosa in tracheal secretions, with negligible effects in pulmonary tissue. Combination of amikacin and fosfomycin with IV meropenem does not increase antipseudomonal pulmonary tissue activity, but it does reduce development of meropenem-resistant P. aeruginosa, in comparison with the sole use of IV meropenem. Our findings imply potential merits for preemptive use of nebulized antibiotics in order to reduce resistance to IV meropenem.

Initial Inflammatory Profile in Community-acquired Pneumonia Depends on Time since Onset of Symptoms.

RATIONALE: Assessment of the inflammatory response can help the decision-making process when diagnosing community-acquired pneumonia (CAP), but there is a lack of information about the influence of time since onset of symptoms. OBJECTIVES: We studied the impact of the number of days since onset of symptoms on inflammatory cytokines and biomarker concentrations at CAP diagnosis in hospitalized patients. METHODS: We performed a secondary analysis in two prospective cohorts including 541 patients in the derivation cohort and 422 in the validation cohort. The time since onset of symptoms was self-reported, and patients were classified as early presenters (<3 d) and nonearly presenters. Biomarkers (C-reactive protein [CRP] and procalcitonin [PCT] in both cohorts) and cytokines in the derivation cohort (IL-1, - 6, -8, -10, and tumor necrosis factor-α) were measured within 24 hours of hospital admission. MEASUREMENTS AND MAIN RESULTS: In early presenters, CRP was significantly lower, whereas PCT, IL-6, and IL-8 were higher. Nonearly presenters showed significantly lower PCT, IL-6, and IL-8 levels. In the validation cohort, CRP and PCT exhibited identical patterns: CRP levels were 36.4% greater in patients with 3 or more days since onset of symptoms than in those with less than 3 days since symptom onset in the derivation cohort and 38.2% in the validation cohort. PCT levels were 40% lower in patients with 3 or more days since onset of symptoms in the derivation cohort and 56% in the validation cohort. CONCLUSIONS: Time since symptom onset modifies the systemic inflammatory profile at CAP diagnosis. This information has relevant clinical implications for management, and it should be taken into account in the design of future clinical trials.

Predictive and prognostic factors in patients with blood-culture-positive community-acquired pneumococcal pneumonia.

In patients with pneumococcal community-acquired pneumonia (CAP), the risk factors for bacteraemia and its impact on outcomes are not fully elucidated. We aimed to compare characteristics of patients with blood-culture-positive versus blood-culture-negative pneumococcal CAP, and to characterise bacteraemic serotypes.We describe a prospective, observational study on nonimmunocompromised patients with pneumococcal CAP, from 1996 to 2013. We define severe pneumonia according to American Thoracic Society/Infectious Diseases Society of America guidelines.Of a total of 917 patients with pneumococcal CAP, 362 had blood-culture-positive pneumococcal pneumonia (BCPPP; 39%). High C-reactive protein (CRP) (≥20 mg·dL(-1)) (odds ratio (OR) 2.36, 95% CI 1.45-3.85), pleural effusion (OR 2.03, 95% CI 1.13-3.65) and multilobar involvement (OR 1.69, 95% CI 1.02-2.79) were independently associated with bacteraemic CAP, while nursing home resident (OR 0.12, 95% CI 0.01-1.00) was found as a protective factor. Despite the clinical differences, BCPPP showed similar outcomes to blood-culture-negative pneumococcal pneumonia (BCNPP). 14% of the serotypes (period 2006-2013) causing bacteraemia are included in pneumococcal conjugate vaccine PVC7, 74% in pneumococcal conjugate vaccine PVC13 and 83% in pneumococcal polysaccharide vaccine PPSV23.Pleural effusion, a high level of CRP and multilobar involvement predicted an increased risk of BCPPP. Although BCPPP patients were more severely ill at admission, mortality was not significantly greater than in BCNPP patients.

Pneumococcal vaccination.

PURPOSE OF REVIEW: Pneumococcal diseases (invasive diseases, pneumonia, otitis media, and sinusitis) are among the most frequent preventable infectious diseases carrying a very high morbidity and case fatality rate worldwide. Pneumococcal vaccination is a key element to reduce the global burden of the disease in children and adult population. Our aim is to discuss current knowledge of the epidemiology of pneumococcal disease and pneumococcal vaccines. RECENT FINDINGS: After the introduction of conjugate vaccines (PCV7 and PCV13), rates of pneumococcal diseases because of vaccine serotypes have decreased considerably among children in the vaccine target and among nonvaccinated children and adults. Results of the Community-Acquired Pneumonia Immunization Trial in Adults demonstrated 45.6% efficacy of PCV13 against the first episode of pneumonia, 45% against first-episode nonbacteremic pneumococcal pneumonia, and 75% against the first episode of invasive pneumococcal diseases in adults older than 65 years. Recommendations for pneumococcal vaccination have changed recently in both the United States and Europe. SUMMARY: The changing epidemiology of pneumococcal diseases should be closely investigated to assess the effectiveness and the usefulness of the current vaccination policies, and to identify future directions for preventing pneumococcal infections.

Community-acquired lung respiratory infections in HIV-infected patients: microbial aetiology and outcome.

We describe the aetiology of community-acquired pneumonia (CAP) in HIV-infected patients, risk factors for bacterial or Pneumocystis jirovecii CAP and prognostic factors of 30-day mortality. This was a prospective observational study of 331 consecutive adult CAP cases in HIV-infected patients (January 2007 to July 2012). 128 (39%) patients had CD4(+) cell counts <200 per mm(3) and 99 (43%) ha HIV RNA levels <200 copies per mL on antiretroviral therapy. Streptococcus pneumoniae was the most frequent microorganism in the group with CD4(+) cell counts ≥ 200 per mm(3); P. jirovecii was the most frequent microorganism in the group with CD4(+) cell counts <200 per mm(3) and in patients with HIV RNA ≥ 200 copies per mL. Predictors of bacterial CAP were: time with symptoms ≤ 5 days (OR 2.6, 95% CI 1.5-4.4), C-reactive protein level ≥ 22 mg·dL(-1) (OR 4.3, 95% CI 2.3-8.2) and hepatitis C virus co-infection (OR 2.3, 95% CI 1.4-3.9). White blood cell count ≤ 4 × 10(12) per L (OR 3.7, 95% CI 1.2-11.5), lactate dehydrogenase (LDH) level ≥ 598 U·L(-1) (OR 12.9, 95% CI 4.2-39.7) and multilobar infiltration (OR 5.8, 95% CI 1.9-19.5) were predictors of P. jirovecii. Overall 30-day mortality was 7%. Appropriate antibiotic treatment (OR 0.1, 95% CI 0.03-0.4), LDH ≥ 598 U·L(-1) (OR 6.2, 95% CI 1.8-21.8) and mechanical ventilation (OR 22.0, 95% CI 6.2-78.6) were the variables independently associated with 30-day mortality. The described predictors may help clinicians to distinguish between bacterial and P. jirovecii pneumonia in patients with suspected or confirmed HIV infection.

Influence of previous use of inhaled corticoids on the development of pleural effusion in community-acquired pneumonia.

RATIONALE: Previous use of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease has been associated with increased risk of community-acquired pneumonia. However, ICS have been associated with fewer pneumonia complications and decreased risk of pneumonia-related mortality. OBJECTIVES: The objective of the study was to assess the influence of previous use of ICS on the incidence of parapneumonic effusion in patients with different baseline respiratory disorders. METHODS: We conducted a single-center cohort study of 3,612 consecutively collected patients diagnosed with community-acquired pneumonia. We assessed clinical, radiographic, and pleural-fluid chemistry and microbiologic variables. Patients were classified according to whether or not they received prior ICS treatment. MEASUREMENTS AND MAIN RESULTS: A total of 633 patients (17%) were treated with corticosteroids before the diagnosis of pneumonia (chronic obstructive pulmonary disease, 54%; asthma, 13%). Incidence of parapneumonic effusion was lower in patients with ICS use compared with non-ICS patients (5% vs. 12%; P < 0.001). After matching according to propensity scores (n = 640), prior treatment with corticosteroids was still significantly associated with a lower incidence of parapneumonic effusion (odds ratio, 0.40; 95% confidence interval, 0.23-0.69; P = 0.001) compared with patients without ICS treatment. Prior ICS treatment was associated with higher levels of glucose (P = 0.003) and pH (P = 0.02), and lower levels of protein (P = 0.01) and lactic acid dehydrogenase (P = 0.007) in the pleural fluid. CONCLUSIONS: Prior treatment with ICS in a population of patients with different respiratory chronic disorders who develop pneumonia is associated with lower incidence of parapneumonic effusion.

The value of biofilm testing to guide antimicrobial stewardship in chronic respiratory diseases.

Introduction: Biofilm production is an important yet currently overlooked aspect of diagnostic microbiology that has implications for antimicrobial stewardship. In this study, we aimed to validate and identify additional applications of the BioFilm Ring Test® (BRT) for Pseudomonas aeruginosa (PA) isolates from patients with bronchiectasis (BE). Materials and methods: Sputa were collected from BE patients who had at least one PA positive culture in the previous year. We processed the sputa to isolate both mucoid and non-mucoid PA, and determined their susceptibility pattern, mucA gene status, and presence of ciprofloxacin mutations in QRDR genes. The Biofilm production index (BPI) was obtained at 5 and 24 hours. Biofilms were imaged using Gram staining. Results: We collected 69 PA isolates, including 33 mucoid and 36 non-mucoid. A BPI value below 14.75 at 5 hours predicted the mucoid PA phenotype with 64% sensitivity and 72% specificity. Conclusion: Overall, our findings suggest that the fitness-cost associated with the mucoid phenotype or ciprofloxacin resistance is shown through a time-dependent BPI profile. The BRT has the potential to reveal biofilm features with clinical implications.

Future Directions in Bronchiectasis Research.

Bronchiectasis treatment is challenging, and many recent randomized controlled trials have failed to prove any clinical improvement. The most reasonable explanation for that problem is the high heterogeneity of patients' groups. For that reason, there is an urgent need to find new biomarkers to better stratify patients. The present chapter addresses the future directions in biomarkers, omics technologies, endotypes, and new treatments toward a personalized medicine in the field of bronchiectasis.

Exacerbations and Changes in Physical Activity and Sedentary Behaviour in Patients with Bronchiectasis after 1 Year.

BACKGROUND: Low physical activity and high sedentary behaviour in patients with bronchiectasis are associated with hospitalisation over one year. However, the factors associated with longitudinal changes in physical activity and sedentary behaviour have not been explored. We aimed to identify clinical and sociodemographic characteristics related to a change in physical activity and sedentary behaviour in patients with bronchiectasis after one year. METHODS: This was a prospective observational study during which physical activity measurements were recorded using a SenseWear Armband for one week at baseline and at one year. At each assessment point, patients were classified as active or inactive (measured as steps per day) and as sedentary or not sedentary (measured as sedentary time). RESULTS: 53 patients with bronchiectasis were analysed, and after one year, 18 (34%) had worse activity and sedentary levels. Specifically, 10 patients became inactive and sedentary. Multivariable analysis showed that the number of exacerbations during the follow-up period was the only outcome independently associated with change to higher inactivity and sedentary behaviour (odds ratio (OR), 2.19; 95% CI, 1.12 to 4.28). CONCLUSIONS: The number of exacerbations in patients with bronchiectasis was associated with changes in physical activity and sedentary behaviour. Exacerbation prevention may appear as a key factor in relation to physical activity and sedentary behaviour in patients with bronchiectasis.

Spectrum of Disease Manifestations in Patients with Selective Immunoglobulin E Deficiency.

BACKGROUND: Selective IgE deficiency (SIgED) has been previously evaluated in selected patients from allergy units. This study investigates the effects of SIgED on the entire population in a hospital setting and sought to delineate in detail the clinical aspects of SIgED. METHODS: A retrospective study of the data obtained from electronic medical records of 52 adult patients (56% female) with a mean age of 43 years and IgE levels of <2.0 kU/L with normal immunoglobulin (Ig) IgG, IgA, and IgM levels, seen at our hospital, without selection bias, from 2010 to 2019. RESULTS: Recurrent upper respiratory infections were recorded in 18 (34.6%) patients, pneumonia was recorded in 16 (30.7%) patients, bronchiectasis was recorded in 16 (30.7%) patients, and asthma was recorded in 10 (19.2%) patients. Eighteen patients (34.6%) suffered autoimmune clinical manifestations either isolated (19%) or combining two or more diseases (15%), Hashimoto's thyroiditis being the most frequent (19%), which was followed by arthritis (10%) and thrombocytopenia and/or neutropenia (5.7%). Other less frequent associations were Graves' disease, primary sclerosing cholangitis, Sjögren's syndrome, and autoimmune hepatitis. Eczematous dermatitis (15.3%), chronic spontaneous urticaria (17.3%), and symptoms of enteropathy (21%) were also highly prevalent. Thirty percent of patients developed malignancies, with non-Hodgkin lymphomas (13.4%) being the most prevalent. CONCLUSIONS: The clinical manifestations of SIgED encompass a variety of infectious, non-infectious complications, and malignancy. Since it cannot be ruled out that some type of selection bias occurred in the routine assessment of IgE serum Ievels, prospective studies are required to better characterize SIgED and to determine whether it should be added to the list of antibody deficiencies.

Development and characterization of a new swine model of invasive pneumococcal pneumonia.

Streptococcus pneumoniae is the most common microbial cause of community-acquired pneumonia. Currently, there are no available models of severe pneumococcal pneumonia in mechanically ventilated animals to mimic clinical conditions of critically ill patients. We studied endogenous pulmonary flora in 4 healthy pigs and in an additional 10 pigs in which we intra-bronchially instilled S. pneumoniae serotype 19 A, characterized by its resistance to penicillin, macrolides and tetracyclines. The pigs underwent ventilation for 72 h. All pigs that were not challenged with S. pneumoniae completed the 72-h study, whereas 30% of infected pigs did not. At 24 h, we clinically confirmed pneumonia in the infected pigs; upon necropsy, we sampled lung tissue for microbiological/histological confirmation of pneumococcal pneumonia. In control pigs, Streptococcus suis and Staphylococcus aureus were the most commonly encountered pathogens, and their lung tissue mean ± s.e.m. concentration was 7.94 ± 20 c.f.u./g. In infected pigs, S. pneumoniae was found in the lungs of all pigs (mean ± s.e.m. pulmonary concentration of 1.26 × 105 ± 2 × 102 c.f.u./g). Bacteremia was found in 50% of infected pigs. Pneumococcal pneumonia was confirmed in all infected pigs at 24 h. Pneumonia was associated with thrombocytopenia, an increase in prothrombin time, cardiac output and vasopressor dependency index and a decrease in systemic vascular resistance. Upon necropsy, microbiological/histological pneumococcal pneumonia was confirmed in 8 of 10 pigs. We have therefore developed a novel model of penicillin- and macrolide-resistant pneumococcal pneumonia in mechanically ventilated pigs with bacteremia and severe hemodynamic compromise. The model could prove valuable for appraising the pathogenesis of pneumococcal pneumonia, the effects associated with macrolide resistance and the outcomes related to the use of new diagnostic strategies and antibiotic or complementary therapies.

Ceftaroline for severe community-acquired pneumonia: A real-world two-centre experience in Italy and Spain.

BACKGROUND: Ceftaroline is one of latest additions to the armamentarium for treating community-acquired pneumonia (CAP). This study aimed to describe the outcome of severe CAP (SCAP) in a cohort of hospitalised patients treated with ceftaroline. METHODS: A retrospective, observational study of patients with SCAP treated with ceftaroline in two hospitals in Spain and Italy. The primary objective was to explore 30-day mortality after diagnosis of SCAP. RESULTS: During the study period the following were observed: there were 89 cases of SCAP treated with ceftaroline and 53 cases used in combination with other antibiotics (60%). Overall, 30-day mortality and clinical failure were 20% (18 of 89) and 36% (32 of 89), respectively. Independent predictors of 30-day mortality were: increasing age (OR for 1 year increase 1.0, 95% CI 1.0-1.1, P 0.043), presence of solid neoplasm (OR 4.0, 95% CI 1.0-15.1, P 0.044) and concomitant therapy with oseltamivir (OR 8.5, 95% CI 1.2°57.3, P 0.029). The only independent predictor of clinical failure was the time elapsing from SCAP diagnosis to ceftaroline therapy (OR for each passing day 1.5, 95% CI 1.1-1.9, P 0.003). The clinical success rate was 64% (57 of 89). In the subgroups of patients with proven Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) infection, clinical success was 83% (10 of 12), 75% (three of four) and 56% (five of nine), respectively. CONCLUSIONS: Considering its spectrum of activity, ceftaroline could represent an important therapeutic option for SCAP. Further studies are needed to identify the precise clinical success rate against MRSA in a larger cohort of patients with SCAP.

Systemic Inflammation during and after Bronchiectasis Exacerbations: Impact of Pseudomonas aeruginosa.

Bronchiectasis is a chronic structural disease associated with exacerbations that provoke systemic inflammation. We aimed to evaluate the systemic acute proinflammatory cytokine and its biomarker profiles during and after exacerbations and its relationship with the severity of episode, microbiological findings, and the bronchiectasis severity index. This prospective observational study compared exacerbation and stable groups. Cytokine (interleukins (IL)-17a, IL-1ß, IL-6, IL 8; tumor necrosis factor-alpha (α)) and high-sensitivity C-reactive protein (hsCRP) levels were determined by multiplex analysis on days 1, 5, 30, and 60 in the exacerbation group and on day 1 in the stable group. We recruited 165 patients with exacerbations, of which 93 were severe (hospitalized). Proinflammatory systemic IL-17a, IL-1ß, IL-8, and tumor necrosis factor-α levels increased similarly on days 1 and 5 in severe and non-severe episodes, but on day 30, IL-17a, IL-8, and IL-6 levels were only increased for severe exacerbations. The highest IL-17a level occurred in patients with chronic plus the acute isolation of Pseudomonas aeruginosa. At 30 days, severe exacerbations were independently associated with higher levels of IL-17 (Odds ratio (OR) 4.58), IL-6 (OR 4.89), IL-8 (OR 3.08), and hsCRP (OR 6.7), adjusted for age, the bronchiectasis severity index, and treatment duration. Exacerbations in patients with chronic P. aeruginosa infection were associated with an increase in IL-17 and IL-6 at 30 days (ORs 7.47 and 3.44, respectively). Severe exacerbations elicit a higher systemic proinflammatory response that is sustained to day 30. Patients with chronic P. aeruginosa infection had impaired IL-17a reduction. IL-17a could be a useful target for measuring systemic inflammation.