Marc J.M. Bonten

Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults.

BACKGROUND Pneumococcal polysaccharide conjugate vaccines prevent pneumococcal disease in infants, but their efficacy against pneumococcal community-acquired pneumonia in adults 65 years of age or older is unknown. METHODS In a randomized, double-blind, placebo-controlled trial involving 84,496 adults 65 years of age or older, we evaluated the efficacy of 13-valent polysaccharide conjugate vaccine (PCV13) in preventing first episodes of vaccine-type strains of pneumococcal community-acquired pneumonia, nonbacteremic and noninvasive pneumococcal community-acquired pneumonia, and invasive pneumococcal disease. Standard laboratory methods and a serotype-specific urinary antigen detection assay were used to identify community-acquired pneumonia and invasive pneumococcal disease. RESULTS In the per-protocol analysis of first episodes of infections due to vaccine-type strains, community-acquired pneumonia occurred in 49 persons in the PCV13 group and 90 persons in the placebo group (vaccine efficacy, 45.6%; 95.2% confidence interval [CI], 21.8 to 62.5), nonbacteremic and noninvasive community-acquired pneumonia occurred in 33 persons in the PCV13 group and 60 persons in the placebo group (vaccine efficacy, 45.0%; 95.2% CI, 14.2 to 65.3), and invasive pneumococcal disease occurred in 7 persons in the PCV13 group and 28 persons in the placebo group (vaccine efficacy, 75.0%; 95% CI, 41.4 to 90.8). Efficacy persisted throughout the trial (mean follow-up, 3.97 years). In the modified intention-to-treat analysis, similar efficacy was observed (vaccine efficacy, 37.7%, 41.1%, and 75.8%, respectively), and community-acquired pneumonia occurred in 747 persons in the PCV13 group and 787 persons in placebo group (vaccine efficacy, 5.1%; 95% CI, -5.1 to 14.2). Numbers of serious adverse events and deaths were similar in the two groups, but there were more local reactions in the PCV13 group. CONCLUSIONS Among older adults, PCV13 was effective in preventing vaccine-type pneumococcal, bacteremic, and nonbacteremic community-acquired pneumonia and vaccine-type invasive pneumococcal disease but not in preventing community-acquired pneumonia from any cause. (Funded by Pfizer; CAPITA ClinicalTrials.gov number NCT00744263.).

Antibiotic treatment strategies for community-acquired pneumonia in adults.

BACKGROUND The choice of empirical antibiotic treatment for patients with clinically suspected community-acquired pneumonia (CAP) who are admitted to non-intensive care unit (ICU) hospital wards is complicated by the limited availability of evidence. We compared strategies of empirical treatment (allowing deviations for medical reasons) with beta-lactam monotherapy, beta-lactam-macrolide combination therapy, or fluoroquinolone monotherapy. METHODS In a cluster-randomized, crossover trial with strategies rotated in 4-month periods, we tested the noninferiority of the beta-lactam strategy to the beta-lactam-macrolide and fluoroquinolone strategies with respect to 90-day mortality, in an intention-to-treat analysis, using a noninferiority margin of 3 percentage points and a two-sided 90% confidence interval. RESULTS A total of 656 patients were included during the beta-lactam strategy periods, 739 during the beta-lactam-macrolide strategy periods, and 888 during the fluoroquinolone strategy periods, with rates of adherence to the strategy of 93.0%, 88.0%, and 92.7%, respectively. The median age of the patients was 70 years. The crude 90-day mortality was 9.0% (59 patients), 11.1% (82 patients), and 8.8% (78 patients), respectively, during these strategy periods. In the intention-to-treat analysis, the risk of death was higher by 1.9 percentage points (90% confidence interval [CI], -0.6 to 4.4) with the beta-lactam-macrolide strategy than with the beta-lactam strategy and lower by 0.6 percentage points (90% CI, -2.8 to 1.9) with the fluoroquinolone strategy than with the beta-lactam strategy. These results indicated noninferiority of the beta-lactam strategy. The median length of hospital stay was 6 days for all strategies, and the median time to starting oral treatment was 3 days (interquartile range, 0 to 4) with the fluoroquinolone strategy and 4 days (interquartile range, 3 to 5) with the other strategies. CONCLUSIONS Among patients with clinically suspected CAP admitted to non-ICU wards, a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies with a beta-lactam-macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality. (Funded by the Netherlands Organization for Health Research and Development; CAP-START ClinicalTrials.gov number, NCT01660204.).

Cost-effectiveness of adult pneumococcal conjugate vaccination in the Netherlands.

The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) demonstrated the efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) in preventing vaccine-type community-acquired pneumonia and vaccine-type invasive pneumococcal disease in elderly subjects. We examined the cost-effectiveness of PCV13 vaccination in the Netherlands. Using a Markov-type model, incremental cost-effectiveness ratios (ICER) of PCV13 vaccination in different age- and risk-groups for pneumococcal disease were evaluated using a societal perspective. Estimates of quality-adjusted life-years (QALYs), costs, vaccine efficacy and epidemiological data were based on the CAPiTA study and other prospective studies. The base-case was PCV13 vaccination of adults aged 65–74 years compared to no vaccination, assuming no net indirect effects in base-case due to paediatric 10-valent pneumococcal conjugate vaccine use. Analyses for age- and risk-group specific vaccination strategies and for different levels of hypothetical herd effects from a paediatric PCV programme were also conducted. The ICER for base-case was €8650 per QALY (95% CI 5750–17 100). Vaccination of high-risk individuals aged 65–74 years was cost-saving and extension to medium-risk individuals aged 65–74 years yielded an ICER of €2900. Further extension to include medium- and high-risk individuals aged ≥18 years yielded an ICER of €3100. PCV13 vaccination is highly cost-effective in the Netherlands. The transferability of our results to other countries depends upon vaccination strategies already implemented in those countries. Vaccinating the elderly with 13-valent pneumococcal conjugate vaccine is highly cost-effective http://ow.ly/NVeui

The impact of age on the efficacy of 13-valent pneumococcal conjugate vaccine in elderly

In a post hoc analysis of the Community-Acquired Pneumonia (CAP) immunization Trial in Adults the model-predicted 13-valent pneumococcal conjugate vaccine efficacy for preventing vaccine-type specific CAP and Invasive Pneumococcal Disease declined from 65% to 40% for subjects being 65 and 75 year olds at the time of vaccination, respectively.

Pneumococcal conjugate vaccine herd effects on non-invasive pneumococcal pneumonia in elderly

BACKGROUND Herd protection from infant pneumococcal conjugate vaccination is well established for invasive pneumococcal disease (IPD) but not for non-IPD pneumococcal community-acquired pneumonia (PCAP). We assessed the contribution of vaccine-serotypes in non-IPD PCAP in adults 65 years and older in the period 2008-2013. METHODS This is a post hoc analysis of two prospective studies from the Netherlands. Serotype specific urinary antigen detection and routine microbiological testing were used to categorize episodes as IPD or non-IPD PCAP caused by 7-valent pneumococcal conjugate vaccine (PCV7), PCV10-7 (three additional PCV10 serotypes), PCV13-10 (three additional PCV13 serotypes), and non-PCV13 serotypes. Proportions per vaccine-serotype group were assessed per year from June 1st to May 31st. Time trends were compared to national IPD data. RESULTS Of 270 non-IPD PCAP episodes with known serotype, PCV7 serotypes decreased from 28% in 2008/2009 to 7% in 2012/2013 (p-value for trend <0.001). No change in PCV10-7 (19% overall) and PCV13-10 (29% overall) serotypes was observed. Non-PCV13 serotypes increased from 30% in 2008/2009 to 37% in 2012/2013 (p-value for trend 0.048). Trends corresponded with national IPD data. CONCLUSION PCV7 serotypes declined in non-IPD PCAP among elderly between 2008 and 2013, comparable to IPD data. No reduction in the additional PCV10 serotypes could be demonstrated within the first two years after PCV10 introduction.

Identification of patients at high risk for Clostridium difficile infection: development and validation of a risk prediction model in hospitalized patients treated with antibiotics

To develop and validate a prediction model for Clostridium difficile infection (CDI) in hospitalized patients treated with systemic antibiotics, we performed a case-cohort study in a tertiary (derivation) and secondary care hospital (validation). Cases had a positive Clostridium test and were treated with systemic antibiotics before suspicion of CDI. Controls were randomly selected from hospitalized patients treated with systemic antibiotics. Potential predictors were selected from the literature. Logistic regression was used to derive the model. Discrimination and calibration of the model were tested in internal and external validation. A total of 180 cases and 330 controls were included for derivation. Age >65 years, recent hospitalization, CDI history, malignancy, chronic renal failure, use of immunosuppressants, receipt of antibiotics before admission, nonsurgical admission, admission to the intensive care unit, gastric tube feeding, treatment with cephalosporins and presence of an underlying infection were independent predictors of CDI. The area under the receiver operating characteristic curve of the model in the derivation cohort was 0.84 (95% confidence interval 0.80-0.87), and was reduced to 0.81 after internal validation. In external validation, consisting of 97 cases and 417 controls, the model area under the curve was 0.81 (95% confidence interval 0.77-0.85) and model calibration was adequate (Brier score 0.004). A simplified risk score was derived. Using a cutoff of 7 points, the positive predictive value, sensitivity and specificity were 1.0%, 72% and 73%, respectively. In conclusion, a risk prediction model was developed and validated, with good discrimination and calibration, that can be used to target preventive interventions in patients with increased risk of CDI.

The Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA): what is the future of pneumococcal conjugate vaccination in elderly?

Pneumococcal community-acquired pneumonia (PCAP) and invasive pneumococcal disease (IPD) are important causes of morbidity and mortality in elderly. In the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA), a randomized double-blind placebo-controlled trial of 84,496 community-dwelling immunocompetent adults over 65 years of age, the 13-valent pneumococcal conjugate vaccine (PCV13) reduced the incidence of first episode of vaccine-type (VT) PCAP with 38 and of VT-IPD with 76% in the modified intention-to-treat population. In The Netherlands, where PCV7 immunization of newborns was introduced in 2007 and replaced by PCV10 in 2011, introduction of PCV13 immunization of elderly--based on 2012 data--would be highly cost effective. However, this is probably different in countries where the VT disease burden has declined more, for instance due to herd effects following child immunization with PCV13. Apart from cost-effectiveness analyses, ethical aspects of PCAP prevention should be taken into account in policy making for pneumococcal vaccination in elderly.

The scrutiny of identifying community-acquired pneumonia episodes quantified bias in absolute effect estimation in a population-based pneumococcal vaccination trial

OBJECTIVES To determine the accurateness of detecting community-acquired pneumonia (CAP) in the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA), a community-based, double-blind, randomized placebo-controlled trial in which the needed to treat (NNT) for prevention of vaccine-type pneumococcal CAP was 1,007 [95% confidence interval (CI): 613, 2,646]. STUDY DESIGN AND SETTING Study participants developing pneumonia were identified in 58 participating hospitals by research nurses (RNs) using local-adapted protocols. In addition, general practitioner (GP) records were screened for hospital referrals for suspected pneumonia. Two independent reviewers determined reasons for not identifying pneumonia episodes, and the NNT adjusted for missed episodes was estimated. RESULTS Of 2,183 hospital referrals with suspected pneumonia detected in GP records, 232 (11%) were admitted outside established screening routes and 102 (5%) were not suspected of pneumonia on admission. Of the remaining 1,849 episodes, 1,374 (63% of all episodes and 74% of identifiable episodes) were identified by RNs. Several causes of missing episodes were identified. After adjustment for missed episodes, the NNT reduced to 634 (95% CI: 386, 1,675). CONCLUSION With the screening procedure, 63% of suspected pneumonia episodes were identified, and the estimated NNT reduced from 1,007 to 634. Root cause analysis of unidentified episodes provides guidance for improving pneumonia detection in future trials.

Predictors of bacteraemia in patients with suspected community-acquired pneumonia

Introduction The diagnostic yield of blood cultures is limited in patients with community-acquired pneumonia (CAP). Yet, positive blood culture results provide important information for antibiotic treatment and for monitoring epidemiologic trends. We investigated the potential of clinical predictors to improve the cost-benefit ratio of obtaining blood cultures. Methods Data from two prospective cohort studies of adults with suspected CAP, admitted to non-ICU wards, were combined. Two models were created, one using readily available parameters and one additionally including laboratory parameters. Results 3,786 patients were included (2,626 (69%) with X-ray confirmed CAP). Blood cultures were obtained from 2,977 (79%) patients (and from 2,107 (80%) with X-ray confirmed CAP). 266 (8.9%) of the patients with a blood culture had bacteraemia. Clinical predictors of bacteraemia were absence of pre-admission antibiotic treatment, pleuritic pain, gastro-intestinal symptoms, tachycardia, tachypnea, hypotension and absence of hypoxia. After including laboratory results in the model, younger age, C-reactive protein, leukocytosis or leukopenia, low thrombocyte count, low sodium level, elevated urea and elevated arterial pH were added, while gastro-intestinal symptoms and hypotension were no longer significant. The area under the receiver operating characteristics curve was 0.66 (95% confidence interval 0.63–0.70) for the first model and 0.76 (95% confidence interval 0.73–0.79) for the second model. Conclusion In conclusion, in patients hospitalized with CAP, bacteraemia was moderately predictable using clinical parameters only. We recommend against the use of a risk prediction model for the decision to obtain blood cultures.

Antibiotics for Community-Acquired Pneumonia in Adults.

n engl j med 373;7 nejm.org august 13, 2015 683 cantly increased rate of stroke in the thrombectomy group. Jolicœur et al. hypothesize that stent deployment in a thrombus-laden coronary lesion may nullify a potential benefit of thrombectomy and that delayed stenting after thrombectomy accompanied by the administration of antithrombotic agents might be more efficacious. The TOTAL Optical Coherence Tomography substudy, which included 214 patients, showed that the residual thrombus volume at the culprit lesion was relatively small after manual thrombectomy,3 a finding that suggests that the failure of thrombectomy is not due to the presence of large amounts of residual thrombus, an observation that may have important implications for future investigative work in this area.