Sex differences in invasive pneumococcal disease and the impact of pneumococcal conjugate vaccination in the Netherlands, 2004 to 2015

Implementation of pneumococcal conjugate vaccines in the Netherlands (PCV7 in 2006 and PCV10 in 2011) for infants caused a shift in serotypes in invasive pneumococcal disease (IPD). We explored sex differences in serotype-specific IPD incidence before and after vaccine introduction. Incidences in the pre-PCV7 (June 2004-May 2006), post-PCV7 (June 2008-May 2011) and post-PCV10 period (June 2013-May 2015), stratified by age, were compared. Incidence was higher in men for all age groups (overall in men: 16.7, 15.5 and 14.4/100,000 and women: 15.4, 13.6 and 13.9/100,000 pre-PCV7, post-PCV7 and post-PCV10, respectively), except for 20-39 year-olds after PCV7 and 40-64 year-olds after PCV10 introduction. After PCV7 and PCV10 introduction, the overall IPD incidence decreased in men aged 20-39 years (from 5.3 pre-PCV7 to 4.7 and 2.6/100,000 post-PCV7 and post-PCV10, respectively), whereas it showed a temporary increase in women (from 3.9/100,000 pre-PCV7 to 5.0/100,000 post-PCV7 and back to 4.0/100,000 post-PCV10) due to replacement disease. PCV10 herd effects were observed throughout, but in women older than 40 years, a significant increase in non-PCV10 serotype offset a decrease in overall IPD incidence. Ongoing surveillance of IPD incidence by sex is important to evaluate the long-term effects of PCV implementation

Target attainment and pharmacokinetics of cefotaxime in critically ill patients undergoing continuous kidney replacement therapy

Objectives Limited data exist about the antimicrobial target attainment and pharmacokinetics of cefotaxime in critically ill patients in the ICU undergoing continuous kidney replacement therapy (CKRT). We conducted a prospective observational study in two large teaching hospitals [Isala Hospital (IH) and Zwolle and Maasstad Hospital (MH)] to investigate target attainment and pharmacokinetics of cefotaxime in patients undergoing CKRT. Patients and methods Patients aged >= 18 years admitted to the ICU treated with IV cefotaxime 1000 mg three times daily (IH) or 4 times daily (MH) were included. Fifteen patients were enrolled in total. Per patient eight cefotaxime plasma and eight ultrafiltrate samples were drawn in IH and four plasma samples in MH on Day 2 of treatment. In ICU patients the recommended antimicrobial target of cefotaxime is a plasma concentration 100% of the time above the MIC. Results In IH 10/11 patients had higher plasma trough concentrations than the MIC breakpoint of Enterobacterales of 1 mg/L (clinical breakpoint for susceptible strains) and 9/11 patients had concentrations above 2 mg/L (clinical breakpoint for resistant strains). All patients (4/4) in MH had higher plasma trough concentrations than 2 mg/L. A sieving coefficient of 0.74 was identified, with a median amount of 40% of cefotaxime eliminated by CKRT. Conclusions We conclude that cefotaxime 1000 mg 3-4 times daily gives adequate plasma concentrations in patients with anuria or oliguria undergoing CKRT. The 1000 mg four times daily dosage is recommended in patients undergoing CKRT with partially preserved renal function to achieve the target

Long-term mortality after IPD and bacteremic versus non-bacteremic pneumococcal pneumonia

Background Short-term mortality after invasive pneumococcal disease (IPD) and pneumococcal pneumonia is high but data on long-term mortality (including the comparison between bacteremic and non-invasive/non-bacteremic pneumococcal pneumonia) within the first years after diagnosis are scarce. Methods Adult patients with ‘non-pneumonia’ IPD and ‘invasive pneumonia’ (from 2004 to 2012) and with ‘bacteremic’ vs ‘non-invasive/non-bacteremic (NI/NB)’ pneumococcal pneumonia (from 2008 to 2012) diagnosed by negative blood culture but a positive urinary antigen test (UAT) were identified in a Dutch hospital. Mortality of patients up to 10 years after diagnosis was compared with age- and sex-matched life-expectancy data of the general population. Multivariable Cox regression analysis was used to study predictors for mortality in invasive pneumonia patients and to adjust for confounders comparing mortality between bacteremic and NI/NB/UAT-positive pneumonia patients. Results Of 228 invasive pneumonia patients 17% died within 30 days and in 30-day survivors cumulative long-term mortality at 1 and 5 years were 16% and 39% as compared with 3% and 15% in age- and sex-matched persons. High mortality was largely dependent on pre-existent comorbidities. In invasive pneumonia patients who survived the first 30 days, age, male gender, chronic cardiovascular disease, malignancy and PCV7 serotype disease were independent predictors for higher long-term mortality. For bacteremic pneumonia patients (n = 128) 30-day mortality was 16% and almost similar to 14% in NI/NB/UAT-positive pneumococcal pneumonia patients (n = 170). In 30-day survivors of bacteremic pneumonia (n = 108, median age 66 years), cumulative mortality at 1 and 3 years were 13% and 29% as compared with 18% and 40% in NI/NB/UAT-positive pneumococcal pneumonia patients (n = 146, median age 67 years) without a significant difference in mortality. Conclusions Approximately 40% of all patients, who survived the first 30 days after presentation with non-pneumonia IPD and pneumococcal pneumonia died within the following 5 years. High long-term mortality was largely dependent on pre-existent comorbidity

Risk and outcomes of invasive pneumococcal disease in adults with underlying conditions in the post-PCV7 era, The Netherlands

BACKGROUND: Immunocompromising conditions and advanced age (≥65 years) are associated with a high risk for invasive pneumococcal disease (IPD). We investigated the risk and outcomes of IPD in adults with underlying conditions in the post-PCV7 era in The Netherlands. METHODS: IPD data from 2008 to 2012 was obtained from the national pneumococcal surveillance system, covering 25% of the Dutch population. Population estimates of underlying conditions were derived from the primary care data (2012). IPD incidence in adults with immunocompromising conditions (high risk group) and non-immunocompromising comorbidities (medium risk group) were compared to the "normal risk group" without diagnosed comorbidities. Case-fatality and ICU admission in the different risk groups was analyzed by logistic regression. Serotype specific propensities to affect high risk group IPD patients were calculated. RESULTS: Adults with a high risk condition have a 18-fold (95% CI 15.6-21.2) and 3-fold (95% CI 2.6-3.9) higher risk compared to the normal risk group for IPD at age 18-64 years and 65 years and older, respectively. In case of a medium risk condition, the risk is 5-fold (95% CI 4.3-5.7) and 2-fold (95% CI 1.9-2.6) higher in age groups 18-64 and ≥65 years old. Likewise, IPD patients with a high or medium risk condition have a higher case-fatality (after adjustment for age, odds ratio: 2-fold (95% CI 1.5-3.5) and 1.4-fold (95% CI 1.0-2.1), respectively). Several serotypes (e.g. 6A, 6B, 23A and 23B) are associated with a significantly higher propensity to cause disease in high risk patients. CONCLUSIONS: The risk for IPD and death in the post-PCV7 era has remained considerably high in adults and elderly with underlying conditions. The identification of serotypes with a high propensity to affect risk groups can be important for selecting (future) vaccine serotypes

Invasive Pneumococcal Disease 3 Years after Introduction of 10-Valent Pneumococcal Conjugate Vaccine, the Netherlands

Three years after a 7-valent pneumococcal conjugate vaccine was replaced by a 10-valent pneumococcal conjugate vaccine in the Netherlands, we observed a decrease in incidence of invasive pneumococcal disease caused by Streptococcus pneumoniae serotypes 1, 5, and 7F. Our data do not support or exclude cross-protection against serotype 19A

Invasive Pneumococcal Disease 3 Years after Introduction of 10-Valent Pneumococcal Conjugate Vaccine, the Netherlands

Three years after a 7-valent pneumococcal conjugate vaccine was replaced by a 10-valent pneumococcal conjugate vaccine in the Netherlands, we observed a decrease in incidence of invasive pneumococcal disease caused by Streptococcus pneumoniae serotypes 1, 5, and 7F. Our data do not support or exclude cross-protection against serotype 19A

Invasive pneumococcal disease: Clinical outcomes and patient characteristics 2-6 years after introduction of 7-valent pneumococcal conjugate vaccine compared to the pre-vaccine period, the Netherlands

Implementation of 7-valent pneumococcal conjugate vaccine (PCV7) in the Dutch national immunization program for infants led to a shift from vaccine to non-vaccine serotypes in invasive pneumococcal disease (IPD) in all age groups. We studied the impact of the serotype shift on clinical syndromes and outcomes. Pneumococcal isolates from hospitalized IPD patients obtained from nine sentinel microbiology laboratories, covering 25% of the Dutch population, were serotyped. Clinical syndromes, outcomes and patient characteristics in the post-PCV7 (2008-2012) period were compared with the pre-PCV7 period (2004-2006). Serotype specific propensity of the association with empyema, meningitis and death was calculated. Invasive pneumonia incidence significantly decreased in children <5 years and elderly ≥65 years, but increased in 5-64 years old from 4.92 to 5.58 cases/100.000/year (RR 1.13 95% CI 0.99-1.29). Empyema incidence significantly increased in elderly 65 years and older from 0.61 to 2.60 cases/100.000/year (RR 4.28 95% CI 1.97-9.33), mainly due to serotype 1. The incidence of meningitis only declined significantly in children <5 years. IPD case-fatality decreased in children <5 years from 5% to 3%, in 5-64 years old from 9% to 7% and in elderly ≥65 years significantly from 22% to 17%, due to lower case-fatality rates for most emerging non-PCV7 serotypes. An increase in empyema incidence was observed in persons ≥65 years old in the post-PCV7 era, mainly due to the emergence of serotype 1, although overall IPD case-fatality decreased. Extended conjugate vaccines that target serotype 1 or serotypes with high case-fatality may offer further reduction of pneumococcal disease burde

Pneumococcal population in the era of vaccination: changes in composition and the relation to clinical outcomes

Background: Vaccination of infants with pneumococcal conjugate vaccines (PCV) has resulted in major shifts in circulating serotypes. Aim: To investigate the impact of PCV7 on the clonal composition of the pneumococcal population, and the relation of clonal lineages and clinical outcome. Materials & methods: By using multiple-locus variable number of tandem repeat analysis, we assessed the pneumococcal populations before (n = 1154), 2-3 years after (n = 1190) and 4-6 years after (n = 1244) the introduction of PCV7 in The Netherlands. Results: We found statistically significant shifts in clonal lineages within serotypes 1 and 12F based on multiple-locus variable number of tandem repeat analysis results after the implementation of PCV7. Within serotype 12F, the increasing clonal lineage was significantly more associated with pneumonia. Conclusion: Shifts in clonal lineages within serotypes could impact the outcomes of pneumococcal disease and fill the niche of the vaccine serotype