M van der Linden

University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany

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Publications (45)148.06 Total impact

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    ABSTRACT: The objectives of this study were to assess the current incidence of invasive pneumococcal disease (IPD) in Poland (2011-2013), where mass vaccination has not been implemented, and to characterize the Streptococcus pneumoniae isolates responsible for invasive infections by determining their serotype distribution and antimicrobial resistance patterns. For all isolates identification, serotyping and antimicrobial minimal inhibitory concentrations determination were performed based on routine techniques. The highest incidence rates were observed among adults older than 85 years old (4.62/100,000) and children under 1 year of age (4.28/100,000). The general case fatality ratio (CFR) was 25.4 %, with the highest CFR in the age group ≥85 years old (59.7 %). The most common serotypes were 3, 14, 19A, 4, 9V, 19F, 1, and 23 F (61.3 % of all isolates). The 10- and 13-valent pneumococcal conjugated vaccines (PCV) covered 46.0 and 71.8 % of all IPD cases, 61.4 and 79.5 % of cases in children under two years, and 60.4 and 78.6 % of cases involving children under five years of age, respectively. The PCV13 and 23-valent polysaccharide vaccine covered 68.7 and 86.0 % of cases in adults >65 years old, respectively. Decreased susceptibility was noted for penicillin (24.8 %), cefotaxime (10.0 %), meropenem (5.0 %), rifampicin (0.8 %), chloramphenicol (4.3 %), erythromycin (29.7 %) and clindamycin (25.6 %). Multi-drug resistance characterized 21.6 % of the pneumococci tested. Despite deficiencies in the Polish surveillance system and strong underestimation of IPD cases, results of the study showed good theoretical coverage of PCV, which should encourage inclusion of anti-pneumococcal conjugate vaccine into the national immunization program.
    12/2014;
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    ABSTRACT: Pneumococcal beta-lactam resistance was first detected in Iceland in the late 1980s, and subsequently peaked at almost 25% of clinical isolates in the mid-1990s largely due to the spread of the internationally-disseminated multidrug-resistant PMEN2 (or Spain6B-2) clone of Streptococcus pneumoniae.
    BMC biology. 06/2014; 12(1):49.
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    ABSTRACT: The multidrug-resistant Streptococcus pneumoniae Taiwan(19F)-14, or PMEN14, clone was first observed with a 19F serotype, which is targeted by the heptavalent polysaccharide conjugate vaccine (PCV7). However, 'vaccine escape' PMEN14 isolates with a 19A serotype became an increasingly important cause of disease post-PCV7. Whole genome sequencing was used to characterise the recent evolution 173 pneumococci of, or related to, PMEN14. This suggested PMEN14 is a single lineage that originated in the late 1980s in parallel with the acquisition of multiple resistances by close relatives. One of the four detected serotype switches to 19A generated representatives of the sequence type (ST) 320 isolates that have been highly successful post-PCV7. A second produced an ST236 19A genotype with reduced resistance to β-lactams owing to alteration of pbp1a and pbp2x sequences through the same recombination that caused the change in serotype. A third, which generated a mosaic capsule biosynthesis locus, resulted in serotype 19A ST271 isolates. The rapid diversification through homologous recombination seen in the global collection was similarly observed in the absence of vaccination in isolates from the Maela refugee camp in Thailand. This sample also allowed variation to be observed within carriage through longitudinal sampling. This suggests some pneumococcal genotypes generate a pool of standing variation that is sufficiently extensive to result in 'soft' selective sweeps: the emergence of multiple related mutants in parallel upon a change in selection pressure, such as vaccine introduction. The subsequent competition between these mutants makes this phenomenon difficult to detect without deep sampling of individual lineages.
    Genome Biology and Evolution 06/2014; · 4.76 Impact Factor
  • M Imöhl, M van der Linden
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    ABSTRACT: Background: Pneumococci remain a major cause of bacterial pneumonia, sepsis and meningitis globally. Methods: The German National Reference Center for Streptococci at the Institute for Medical Microbiology of the University Hospital RWTH Aachen, Germany, has carried out surveillance studies on invasive pneumococcal disease (IPD) since 1992. This report is based on IPD-cases from adults and children, received between July 1992 and June 2013 and July 1997 and June 2013 respectively. Results: From 1997-2006 the proportion of infections among children ≤ 23 months of age with serotypes included in the 7-valent vaccine was about 65 %. Since the start of childhood vaccination in 2006 the percentage has continuously decreased, reaching < 5 % in 2012 /2013. Also among adults, for whom conjugate vaccination was not indicated, this percentage decreased from 40-45 % in 1992-2006 to about 8 % in 2012 /2013. This phenomenon is denoted as herd protection. The resistance rate against Penicillin G remained under 4 % among children and under 2.5 % among adults over the whole study period. Since 2005 /2006 macrolide resistance levels have decreased to about 5 % among children and 8 % among adults. Conclusion: The continuous decrease of vaccine serotypes as well as the decreasing IPD incidence since the beginning of childhood vaccination document the success of pneumococcal conjugate vaccination.
    DMW - Deutsche Medizinische Wochenschrift 06/2014; 139(25/26):1346-1351. · 0.65 Impact Factor
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    ABSTRACT: Infections due to pneumococci especially in the elderly are vastly underestimated, e.g., because non-invasive infections such as pneumonia may appear with only few symptoms. Sequential vaccination with the pneumococcal conjugate vaccine PCV13, followed by the 23-valent polysaccharide vaccine, is considered as the best preventive measure for individual protection, even though clinical study data demonstrating the efficacy of this sequence are not yet available. Increase of "awareness" by use of computer-based reminder functions may result in a significant improvement of vaccination compliance.
    Zeitschrift fur Gerontologie und Geriatrie. 05/2014;
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    ABSTRACT: The use of trimethoprim in treatment of Streptococcus pyogenes infections has long been discouraged because it was widely believed that this pathogen is resistant to this antibiotic. To gain more insight into the extent and molecular basis of trimethoprim resistance in S. pyogenes we have tested isolates from India and Germany and sought for the factors that conferred the resistance. Resistant isolates were identified in tests for trimethoprim or trimethoprim/sulfamethoxazole (SXT) susceptibility. Resistant isolates were screened for known horizontally transferable trimethoprim insensitive dihydrofolate reductase (dfr) genes dfrG, dfrF, dfrA, dfrD and dfrK. The nucleotide sequence of the intrinsic dfr was determined for resistant isolates lacking the horizontally transferable genes. Based on tentative criteria 69 out of 268 isolates (25.7%) from India were resistant to trimethoprim. Occuring in 42 of the 69 resistant isolates (60.9%) dfrF was more frequent than dfrG (23 isolates, 33.3%) in India. The dfrF-gene was also present in a collection of SXT-resistant isolates from Germany, in which it was the only detected trimethoprim resistance factor. DfrF caused resistance in 4 out of 5 trimethoprim resistant isolates from the German collection. An amino acid substitution in the intrinsic dihydrofolate reductase known from trimethoprim resistant Streptococcus pneumoniae, conferred resistance to S. pyogenes isolates of emm-type 102.2, which lacked other aforementioned dfr genes. Trimethoprim may be more useful in treatment of S. pyogenes infections than previously thought. However, the herein described factors may lead to a rapid development and spread of resistance to this antibiotic agent in S. pyogenes.
    Antimicrobial Agents and Chemotherapy 02/2014; · 4.57 Impact Factor
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    ABSTRACT: Viridans group (VGS) or bovis group streptococci (BGS) are the major causes for streptococcal infective endocarditis (IE). However, the causative isolates are not sufficiently characterized. Using multilocus sequence analysis we have examined VGS and BGS (VGS/BGS) isolates that caused IE in southern India and Germany, two distant geographic regions with a contrasting IE epidemiology. Other than in Germany, the majority of patients (68%) in Chennai, southern India had an underlying rheumatic heart disease (RHD). In accord with the high prevalence of RHD in the younger population and with the expansive age structure of India, the median age (24 years) of the VGS/BGS endocarditis patients was lower than in Germany (63 years), where RHD is rare and the age structure is contractive. Both in Germany and in southern India, the majority of cases were caused by mitis group streptococci, however, with considerable differences in the spectra of causative (sub)species. BGS endocarditis was more frequent in Germany. The spectrum of VGS/BGS that cause IE differs considerably between distant geographic regions in which different predisposing conditions prevail. Therefore, improved microbiological diagnosis in IE may facilitate determination of the optimal therapy.
    International journal of medical microbiology: IJMM 10/2013; · 4.54 Impact Factor
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    ABSTRACT: BACKGROUND: The antihypertensives reserpine and verapamil are also inhibitors of pneumococcal efflux pumps. We addressed the following questions: (i) Do verapamil and reserpine influence the mutation ratio of pneumococci in the presence of ciprofloxacin? (ii) At which concentrations does this occur? (iii) Is this limited to isolates with efflux phenotype? METHODS: 14 clinical isolates, nested in 6 genetically similar clusters, were used, 7 strains with efflux and 7 without. The mutation ratio in the presence of ciprofloxacin (3×MIC) and increasing concentrations of reserpine and verapamil was determined and the quinolone-resistance determining regions (QRDR) of selected mutants were sequenced. Analysis of the efficacy was performed using a mixed linear model, supported by descriptive statistics. RESULTS: Reserpine and verapamil reduced the mutation ratio of QRDR in the presence of ciprofloxacin with the required concentration for a reduction ≥50% of 1mg/l for reserpine and 50mg/l for verapamil. The mutation prevention effect is not limited to, but is more pronounced in efflux positive phenotypes. CONCLUSION: Reserpine and verapamil can prevent the selection of ciprofloxacin resistant isolates by reduction of the mutation ratio, particularly in strain with an efflux phenotype. However, the required concentrations are too toxic for clinical use.
    International journal of medical microbiology: IJMM 03/2013; · 4.54 Impact Factor
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    M W Pletz, M van der Linden, J P Fobiwe, C Theilacker
    DMW - Deutsche Medizinische Wochenschrift 02/2013; 138(5):185-7. · 0.65 Impact Factor
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    ABSTRACT: BACKGROUND: African Pygmies have many risk factors for invasive pneumococcal disease (IPD), such as low socioeconomic status and low quality of health care. We characterized Streptococcus pneumoniae from Gabonese Pygmies and analyzed risk factors for S. pneumoniae carriage to improve prophylaxis and therapy of IPD in this neglected, remotely living African community. METHODS: Nasopharyngeal carriage of S. pneumoniae, susceptibility, serotypes and risk factors for IPD were assessed in 103 Pygmies in a cross-sectional study. RESULTS: The carriage rate was 37% (n = 38), with the highest proportion (79%, n = 11) in children between two and four years (n = 14). The predominant serotypes were 15A (24%, n = 9), 11A (16%, n = 6) and 6A (13%, n = 5). Non-susceptibility was detected against penicillin (Clinical and Laboratory Standards Institute; CLSI) meningitis breakpoints; (18%, n = 7), trimethoprim/sulfamethoxazole (61%, n = 23), tetracycline (55%, n = 21) and chloramphenicol (3%, n = 1). Among adult participants (n = 51), 69% (n = 35) regularly consumed alcohol and 75% (n = 38) reported to smoke cigarettes. CONCLUSION: The high proportion of nicotine and drug abuse might increase the risk of IPD. The unusual serotypes challenge a broad coverage by currently marketed vaccines; the broad antibiotic resistance limits the choice of therapy for S. pneumoniae infection.
    Transactions of the Royal Society of Tropical Medicine and Hygiene 11/2012; · 1.82 Impact Factor
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    ABSTRACT: To assess the comparative public health and budget impact over 5 years of several pneumococcal vaccination strategies (23-valent pneumococcal polysaccharide vaccine [PPV23] and/or 13-valent pneumococcal conjugate vaccine [PCV13]) in Germany, within the context of changing invasive pneumococcal disease (IPD) incidence over time. A multi-cohort, population-based Markov model was developed. Uncertainty around vaccine effectiveness, costs and IPD incidence change was handled through scenario analyses. Between 2012 and 2016, the introduction of PCV13 in adults, compared with the use of PPV23, would be associated with a net estimated budget increase of €59.7 million (+6.7%) to €151.6 million (+13.7%). Impact on IPD incidence ranged from -113 cases (-0.8%) to +298 cases (+2.8%). Introducing PCV13 in adults is expected to significantly affect healthcare budgets. Adult vaccination with PPV23 remains the optimal vaccination strategy from public health and budget perspectives.
    Expert Review of Pharmacoeconomics & Outcomes Research 10/2012; · 1.67 Impact Factor
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    ABSTRACT: The introduction of routine infant vaccination against pneumococcal disease has resulted in a decreased overall invasive pneumococcal disease incidence in adults but also a change in invasive pneumococcal disease serotypes. This study aimed to assess the cost-effectiveness of 23-valent pneumococcal polysaccharide vaccine (PPV23) in Germany in this context. A population-based Markov model was developed. A cohort of adults currently eligible for vaccination was followed until death. Adult vaccination with PPV23 was associated with an incremental cost-effectiveness ratio of €17,065/quality-adjusted life years gained from the third-party payer's perspective. Univariate sensitivity analyses showed that the incremental cost-effectiveness ratio was below €50,000/quality-adjusted life years gained in most test scenarios. The model suggests that adult PPV23 vaccination is cost-effective in Germany, due to its broad serotype coverage. This is despite epidemiological changes in Streptococcus pneumoniae serotypes caused by wider use of pneumococcal conjugate vaccines during childhood.
    Expert Review of Pharmacoeconomics & Outcomes Research 10/2012; · 1.67 Impact Factor
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    ABSTRACT: The burden of invasive pneumococcal disease in young children decreased dramatically following introduction of the 7-valent pneumococcal conjugate vaccine (PCV7). The epidemiology of S. pneumoniae now reflects infections caused by serotypes not included in PCV7. Recently introduced higher valency pneumococcal vaccines target the residual burden of invasive and non-invasive infections, including those caused by serotypes not included in PCV7. This review is based on presentations made at the European Society of Pediatric Infectious Diseases in June 2011. Surveillance data show increased circulation of the non-PCV7 vaccine serotypes 1, 3, 6A, 6C, 7 F and 19A in countries with routine vaccination. Preliminary evidence suggests that broadened serotype coverage offered by higher valency vaccines may be having an effect on invasive disease caused by some of those serotypes, including 19A, 7 F and 6C. Aetiology of community acquired pneumonia remains a difficult clinical diagnosis. However, recent reports indicate that pneumococcal vaccination has reduced hospitalisations of children for vaccine serotype pneumonia. Variations in serotype circulation and occurrence of complicated and non-complicated pneumonia caused by non-PCV7 serotypes highlight the potential of higher valency vaccines to decrease the remaining burden. PCVs reduce nasopharyngeal carriage and acute otitis media (AOM) caused by vaccine serotypes. Recent investigations of the interaction between S. pneumoniae and non-typeable H. influenzae suggest that considerable reduction in severe, complicated AOM infections may be achieved by prevention of early pneumococcal carriage and AOM infections. Extension of the vaccine serotype spectrum beyond PCV7 may provide additional benefit in preventing the evolution of AOM. The direct and indirect costs associated with pneumococcal disease are high, thus herd protection and infections caused by non-vaccine serotypes both have strong effects on the cost effectiveness of pneumococcal vaccination. Recent evaluations highlight the public health significance of indirect benefits, prevention of pneumonia and AOM and coverage of non-PCV7 serotypes by higher valency vaccines. Routine vaccination has greatly reduced the burden of pneumococcal diseases in children. The pneumococcal serotypes present in the 7-valent vaccine have greatly diminished among disease isolates. The prevalence of some non-vaccine serotypes (e.g. 1, 7 F and 19A) has increased. Pneumococcal vaccines with broadened serotype coverage are likely to continue decreasing the burden of invasive disease, and community acquired pneumonia in children. Further reductions in pneumococcal carriage and increased prevention of early AOM infections may prevent the evolution of severe, complicated AOM. Evaluation of the public health benefits of pneumococcal conjugate vaccines should include consideration of non-invasive pneumococcal infections, indirect effects of vaccination and broadened serotype coverage.
    BMC Infectious Diseases 09/2012; 12:207. · 3.03 Impact Factor
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    ABSTRACT: Pneumococcal pneumonia is still an important cause of mortality. The objective of this study was to compare frequency, clinical presentation, outcome and vaccination status of patients with pneumococcal community-acquired pneumonia (CAP) to CAP due to other or no detected pathogen based on data of the German Network for community-acquired pneumonia (CAPNETZ). Demographic, clinical and diagnostic data were recorded using standardized web-based data acquisition. Standardized microbiological sampling and work-up were conducted in each patient. 7400 patients with CAP from twelve clinical centers throughout Germany were included. In 2259 patients (32 %) a pathogen was identified, Streptococcus pneumonia being the most frequent (n = 676, 30 % of all patients with identified pathogens). Compared to those with non-pneumococcal pneumonia, patients with pneumococcal pneumonia were more frequently admitted to hospital (80 % vs. 66 %, p < 0.001), had higher CURB score values on admission, had more frequently pleural effusion (19 % vs. 14 %, p = 0.001) and needed more frequently oxygen insufflation (58 % vs. 44 %, p < 0.001). There was no relevant difference in overall mortality. Pneumococcal pneumonia was associated with a more severe clinical course demanding more medical resources as compared to non-pneumococcal pneumonia.
    Pneumologie 08/2012; 66(8):470-5.
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    ABSTRACT: The population of the Region (Central Europe, Eastern Europe, and Israel) is ageing, necessitating preventative programmes to maintain a healthy and active lifestyle in older age groups. Invasive pneumococcal disease (including bacteremic pneumonia, bacteremia without a focus, and meningitis) has higher incidence, morbidity and mortality in older adults and is a substantial public health burden in the ageing population. Surveillance in the Region establishes a significant burden in older adults of invasive pneumococcal disease (IPD), which still appears to be under-estimated as compared with other countries, and this warrants an improvement in surveillance systems. The largest proportion of IPD in adults is bacteremic pneumonia. Community-acquired pneumonia (CAP), largely attributable to S. pneumoniae, can be bacteremic or non-bacteremic; the non-bacteremic forms of CAP also represent a significant burden in the Region. The burden of pneumococcal disease can be reduced with programmes of effective vaccination. Recommendations on pneumococcal vaccination in adults vary widely across the Region. The main barrier to implementation of vaccination programmes is low awareness among healthcare professionals on serious heatlh consequences of adult pneumococcal disease and of vaccination options. The Expert Panel calls on healthcare providers in the Region to improve pneumococcal surveillance, optimize and disseminate recommendations for adult vaccination, and support awareness and education programmes about adult pneumococcal disease.
    Central European journal of public health 06/2012; 20(2):121-5. · 0.80 Impact Factor
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    ABSTRACT: Clin Microbiol Infect ABSTRACT: Sickle cell anaemia (SCA) is a haemoglobin disorder that alters the deformability of erythrocytes through abnormal polymerization of haemoglobin. Children with SCA have an increased risk of infections with encapsulated bacteria. To guide the antibiotic prophylaxis and vaccinations in children with SCA in Gabon, we characterized Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae from children with and without SCA. We performed a cross-sectional study and compared nasal and pharyngeal S. pneumoniae, Staph. aureus and H. influenzae isolates from SCA children (n = 73) with comparators matched for age, residence and sex (n = 143) in a matched-comparison analysis. The resistance pattern and capsular type were identified for each isolate. The total carriage rate for S. pneumoniae, Staph. aureus and H. influenzae was 13.8%, 46.7% and 12.5%, respectively, and did not differ between groups (p >0.05). The mean number of days under antibiotic treatment in the past year was higher in children with SCA than in controls (penicillin: 70.1 vs 0.1 days, p 0.00002). The total non-susceptibility rate was 30% for oral and parenteral (meningitis) penicillin in S. pneumoniae, resistance rates were 1.6% for oxacillin in Staph. aureus and 14.8% for ampicillin in H. influenzae. Susceptibility to antibiotic agents and distribution of capsular types did not differ significantly between both groups. In conclusion, carriage and resistance rates are similar in children with and without SCA. Our data provide the basis to guide empiric therapy of invasive diseases caused by S. pneumoniae, Staph. aureus and H. influenza in children in Gabon.
    Clinical Microbiology and Infection 02/2012; · 4.58 Impact Factor
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    ABSTRACT: The surveillance and prevention of invasive bacterial infections requires flexible strategic coordination of all involved health-care professionals. For this purpose, the German National Reference Centres for Meningococci, Streptococci and the Consultant Laboratories for Haemophilus influenzae and diphtheria have formed the Reference Network for Invasive bacterial infections (IBI). The 5th Würzburg Workshop on Meningococcal Diseases 2010 provided the network with a forum for the interdisciplinary exchange between scientists, public health professionals, medical microbiologists and clinicians. The topics covered the analysis of surveillance data for meningococcal disease in the last decade, as well as methods to control for antibody response following vaccination, including a serum bactericidal antibody (SBA) assay, and the development of new vaccines that also include the most common serogroup B. The presentation on diphtheria showed that this rare disease in Germany has become a diagnostic challenge, and that apart from the classical pathogen also toxigenic C. ulcerans strains must be considered. Due to the successful vaccination against Hib, H. influenzae disease has changed from a classical childhood disease to an infection of elderly people mainly caused by unencapsulated strains. Following the introduction of vaccines, changes in the serotype distribution and antibiotic resistance profiles have become apparent for S. pneumoniae infections. The epidemiological data were complemented by clinical aspects concerning the vaccination of immunocompromised children.
    Das Gesundheitswesen 12/2011; · 0.62 Impact Factor
  • Value in Health 11/2011; 14(7). · 2.19 Impact Factor
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    ABSTRACT: A few international pneumococcal clones dominate the population of antibiotic-resistant pneumococci. Despite the scientific paradigm that a loss in fitness is the price for acquisition of resistance, these clones spread successfully. One hundred fifty-four isolates from adult patients with community-acquired pneumonia (CAP) were analyzed. Thirty percent showed a close relationship to international clones and had fitness equal to or exceeding that of other strains (P = 0.015); these factors may result in the endurance of these strains despite a reduction of antibiotic usage.
    Antimicrobial Agents and Chemotherapy 08/2011; 55(10):4915-7. · 4.57 Impact Factor
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    ABSTRACT: Vaccination is the only public-health measure likely to reduce the burden of pneumococcal diseases. In 2010, a group of European experts reviewed evidence on the burden of pneumococcal disease and the immunogenicity, clinical effectiveness and cost-effectiveness of vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV23). They also considered issues affecting the future use of PPV23 and pneumococcal conjugate vaccines in the elderly and adults at high risk of pneumococcal disease. PPV23 covers 80-90% of the serotypes responsible for invasive pneumococcal disease in Europe. Primary vaccination and revaccination with PPV23 are well tolerated, induce robust, long-lasting immune responses in elderly adults and are cost effective. Ensuring protection against pneumococcal disease requires monitoring of the changing epidemiology of pneumococcal serotypes causing invasive pneumococcal disease and improving vaccine coverage. In the future, it will be critically important for pneumococcal vaccination recommendations for elderly adults to be based on comparative evaluations of PPV23 and newer pneumococcal conjugate vaccines with regard to their long-term immunogenicity, clinical effectiveness and cost-effectiveness.
    Expert Review of Vaccines 08/2011; 10(8):1143-67. · 4.22 Impact Factor

Publication Stats

497 Citations
148.06 Total Impact Points

Institutions

  • 2005–2014
    • University Hospital RWTH Aachen
      Aachen, North Rhine-Westphalia, Germany
  • 2012
    • Universitätsklinikum Jena
      Jena, Thuringia, Germany
    • Medical Research Unit
      Lambaréné, Moyen-Ogooué, Gabon
  • 2011
    • Wellcome Trust Sanger Institute
      Cambridge, England, United Kingdom
  • 2010
    • Universität Heidelberg
      • Institute of Medical Microbiology and Hygiene
      Heidelberg, Baden-Wuerttemberg, Germany
    • Universitair Ziekenhuis Leuven
      Louvain, Flanders, Belgium
  • 2007
    • RWTH Aachen University
      • Institute of Medical Microbiology
      Aachen, North Rhine-Westphalia, Germany