Pneumococcal vaccination: what have we learnt so far and what can we expect in the future?

Individuals <2 years and ≥ 50 years of age, as well as those with other specific risk factors, are especially vulnerable to invasive pneumococcal disease (IPD). Conjugate vaccines have been developed against encapsulated bacteria such as Streptococcus pneumoniae to provide improved immune responses. The 7-valent pneumococcal conjugate vaccine (PCV7) has significantly reduced the burden of vaccine-type pneumococcal diseases in children, including invasive disease and pneumonia and acute otitis media. There have also been significant declines in antimicrobial resistance in 7-valent vaccine serotypes and carriage of S. pneumoniae in the post-PCV7 era. Two to three years after the introduction of PCV13, there is emerging, global evidence of a reduced burden of pneumococcal diseases in children, including declines in IPD (UK and Germany) and nasopharyngeal carriage of PCV13 serotypes (Portugal and France). The functional immunogenicity of PCV13 in individuals ≥ 50 years of age has been demonstrated in clinical trials in comparison with the 23-valent pneumococcal polysaccharide vaccine and for children and adults 6 to 49 years of age. Between 2011 and 2013, PCV13 received market authorisation by the European Medicines Agency (EMA) for these additional age groups and is now available in Europe for the prevention of pneumococcal disease in all age groups.

Penicillin susceptibility breakpoints for Streptococcus pneumoniae and their effect on susceptibility categorisation in Germany (1997-2013).

Continuous nationwide surveillance of invasive pneumococcal disease (IPD) was conducted in Germany. From July 1, 1997, to June 30, 2013, data on penicillin susceptibility were available for 20,437 isolates. 2,790 of these isolates (13.7 %) originate from patients with meningitis and 17,647 isolates (86.3 %) are from non-meningitis cases. A slight decline in isolates susceptible at 0.06 and 0.12 µg/ml can be noticed over the years. Overall, 89.1 % of the isolates had minimum inhibitory concentrations (MICs) of ≤0.015 µg/ml. In 2012/2013, the first three isolates of Streptococcus pneumoniae with MICs of 8 µg/ml were found. The application of different guidelines with other MIC breakpoints for the interpretation of penicillin resistance leads to differences in susceptibility categorisation. According to the pre-2008 Clinical and Laboratory Standards Institute (CLSI) interpretive criteria, 5.3 % of isolates overall were intermediate and 1.4 % were resistant to penicillin. Application of the 2008-2014 CLSI interpretive criteria resulted in 7.6 % resistance among meningitis cases and 0.5 % intermediate resistance in non-meningitis cases. Referring to the 2009-2014 European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints, 7.6 % of the isolates in the meningitis group were resistant to penicillin. In the non-meningitis group, 6.1 % of the isolates were intermediate and 0.5 % were resistant. These differences should be kept in mind when surveillance studies on pneumococcal penicillin resistance are compared.

Serotype distribution in pneumococcal acute otitis media with ruptured tympanic membrane or sepsis in Germany.

This retrospective analysis examined the pneumococcal serotype distribution of acute otitis media in Germany from 1995 to 2007. Data from the German National Reference Centre for Streptococci included 512 cases of pneumococcal otitis media in children and adults. Infections were mainly seen in children aged <5 years, who represented 67.0% of all reported cases. Most isolates (86.7%) were from spontaneous ruptures of the tympanum; 11.1% of the isolates were from otogenic sepsis or meningitis. Serotype 19F was the leading serotype (21.5%); serotype 3 (13.9%) was also often encountered. In children aged <5 years, the 7-valent, 10-valent, and 13-valent pneumococcal conjugate vaccines covered 54.3%, 60.2%, and 84.6% of the serotypes, respectively. Reduced penicillin susceptibility (minimum inhibitory concentration >or=0.1 mg/l) was seen in 11.0% of strains; 22.4% of strains were resistant to macrolides. Although based on a very limited selection of acute otitis media isolates, this analysis provides an estimate of the pneumococcal serotypes responsible for otitis media in Germany and underscores the need for future prospective studies.

Risk factor analysis for pneumococcal meningitis in adults with invasive pneumococcal infection.

Pneumococcal meningitis is a subgroup of invasive pneumococcal disease with a case-fatality rate of up to 30% and long-term sequelae in more than 50% of cases in adults in developed countries. We aimed to determine risk factors for this particular form of pneumococcal disease. We conducted a prospective population-based laboratory study of invasive pneumococcal disease in adults in North-Rhine-Westphalia, Germany from February 2001 to August 2006. All isolates underwent serotyping and susceptibility testing at the National Reference Centre for Streptococci in Aachen, Germany. Data were analysed using multiple linear regression. A total of 1043 isolates from bacteraemia and 131 isolates from meningitis were included into the study. Serotype 23F and being female were independent risk factors for pneumococcal meningitis. Being 60 years and serotype 1 were associated with a reduced odds ratio. Season, penicillin and macrolide resistance were not statistically associated with CNS involvement.

Distribution of emm types among group A streptococcal isolates from Serbia.

This is the first study concerning the molecular epidemiology of group A streptococcus in Serbia and includes 145 isolates from patients with various infections during the period 2001-2007. The emm types, superantigen profile and susceptibility pattern were determined. Among 31 emm types identified, the most prevalent were emm 6, emm 12, emm 1, and emm 58. All isolates showed uniform antimicrobial susceptibility to all tested antibiotics, with the exception of tetracycline and erythromycin (41% and 0.7% resistant strains, respectively). Significant heterogeneity of emm types was found, with a high frequency of emm 6 and emm 58, as well as a considerable prevalence of tetracycline resistance, and a low level of macrolide resistance.

Adult invasive pneumococcal disease between 2003 and 2006 in North-Rhine Westphalia, Germany: serotype distribution before recommendation for general pneumococcal conjugate vaccination for children <2 years of age.

A laboratory-based surveillance study of adult invasive pneumococcal disease was conducted in North-Rhine Westphalia, Germany's most populous federal state, with approximately 18 million inhabitants. Invasive isolates (n = 519) were obtained between 2003 and 2006, before the general recommendation for vaccination of German children <2 years with the pneumococcal conjugate vaccine was issued at the end of July 2006. Penicillin G resistance was observed in 5% of meningitis cases. In the non-meningitis group, only intermediately resistant strains were detected (0.4%). Intermediate resistance to cefotaxime occurred both in meningitis cases (1.7%) and non-meningitis cases (0.4%). Non-susceptibility rates (intermediate resistance and resistance) were 16.2% for macrolides, 10.9% for trimethoprim-sulphamethoxazole, 5.0% for tetracycline, 3.9% for clindamycin, and 0.4% for levofloxacin. All isolates were susceptible to amoxycillin (non-meningitis) and telithromycin. The leading serotypes were serotypes 14 (14.3%), 7F (9.4%), 3 (9.2%), 4 (8.7%) and 1 (8.1%). Serotype coverage for the seven-valent conjugate vaccine was 43.9%. For the ten-valent and 13-valent vaccines (in development), the coverages were 61.8% and 76.7%, respectively. The 23-valent polysaccharide vaccine had a coverage of 91.1%.

The antimicrobial resistance profile of Streptococcus pneumoniae.

Antibacterial resistance in pneumococci is increasing worldwide, primarily against beta-lactams and macrolides. Understanding the role played by molecular determinants of resistance, transformation and competence in the evolution of Streptococcus pneumoniae is important in addressing this trend. Data from the Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT) study indicate that about 40% of pneumococci display multidrug-resistant phenotypes (resistance to three or more antibiotics), with highly variable prevalence rates observed in different countries. Alterations in the structure of six penicillin-binding proteins (PBPs) have been described in S. pneumoniae (1a, 1b, 2x, 2a, 2b and 3), enabling resistance to beta-lactam antibiotics. Mechanisms conferring macrolide resistance include resistance mediated through the erm(B) gene, which results in macrolide-lincosamide-streptogramin B resistance, or through the mef(A) gene, which encodes an antibiotic efflux pump. Another variant, mef(E), is also expressed in S. pneumoniae; both mef(A) and mef(E) variants are associated with strains belonging to serotype 14. In addition to the selection pressure resulting from misuse of antibiotics, widespread vaccination programmes may contribute to changing pneumococcal epidemiology. Since the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7), the rate of invasive pneumococcal disease due to PCV7 serotypes has declined significantly in many countries, but some countries have reported an increase in non-PCV7 serotypes. This phenomenon, termed 'replacement', is associated with certain pneumococcal serotypes or clones (e.g. serotype 19A). Whether novel 'vaccine escape recombinant' pneumococcal strains are emerging or changes in distribution are part of a secular cycle remains to be determined.

Epidemiology of invasive Streptococcus pyogenes infections in Germany, 1996-2002: results from a voluntary laboratory surveillance system.

A nationwide voluntary laboratory-based surveillance study of invasive Streptococcus pyogenes (group A streptococcus; GAS) infections was conducted in Germany between 1996 and 2002. Demographical and clinical information concerning the patients was obtained from the medical files. Multiple logistic regression analysis was used to determine risk-factors for fatal outcome. Invasive isolates were obtained from 475 patients, with 251 (52.8%) of the isolates cultured from blood. The most frequent emm types were emm1 (36.4%), emm28 (8.8%) and emm3 (8%). The speA, speC and ssa genes were present at variable frequencies in different emm types. The highest frequencies of speA and speC were found in emm1 (speA, 93.6%) and emm4 (speC, 94.7%), respectively. The estimated annual incidence of invasive GAS disease for 1997-2002 was 0.1 cases/100 000 individuals. This apparently low incidence rate might be explained by the voluntary nature of the surveillance system, resulting in relatively few cases being referred to the laboratory. Complete clinical information was available for 165 cases. The overall case fatality rate was 40.6%, and was highest (65.2%) in the group aged 60-69 years. Shock, an age of >or=30 years and adult respiratory distress syndrome were predictors of a fatal outcome in a multiple logistic regression analysis. Overall, 6.7% of the cases were considered to be nosocomial, and nine cases of puerperal sepsis were observed. The study underscores the importance of invasive S. pyogenes disease in Germany.

Sepsis severity predicts outcome in community-acquired pneumococcal pneumonia.

Easily performed prognostic rules are helpful for guiding the intensity of monitoring and treatment of patients. The aim of the present study was to compare the predictive value of the sepsis score and the Confusion, Respiratory rate (> or =30 breaths.min(-1)), Blood pressure (systolic value <90 mmHg or diastolic value < or =60 mmHg) and age > or =65 yrs (CRB-65) score in 105 patients with community-acquired pneumococcal pneumonia. In addition, the influence of timing of the antimicrobial treatment on outcome was investigated. The sepsis and the CRB-65 scores were used to allocate patients to subgroups with low, intermediate and high risk. Comparable, highly predictive values for mortality were found for both scores (sepsis score versus CRB-65): 1) low-risk group, 0 versus 0%; 2) intermediate-risk group, 0 versus 8.6%; 3) high-risk group, 30.6 versus 40%, with an area under the curve of 0.867 versus 0.845. Patients with ambulatory antibiotic pre-treatment had less severe disease with a lower acute physiology score, lower white blood cell count and a faster decline of C-reactive protein levels. No pre-treated patient died. In summary, both scores performed equally well in predicting mortality. The prediction of survival in the intermediate-risk group might be more accurate with the sepsis score. Pre-hospital antibiotic treatment was associated with less severe disease.

Cost-effectiveness of pneumococcal vaccination for prevention of invasive pneumococcal disease in the elderly: an update for 10 Western European countries.

Pneumococcal vaccine is effective in preventing invasive pneumococcal disease in adults >or=65 years of age, but it is not widely used in Western Europe. In this study, data from an earlier (1995) cost-effectiveness study on Belgium, France, Scotland, Spain, and Sweden are updated, and data on five new countries--Denmark, the UK (specifically, England and Wales), Germany, Italy and The Netherlands--are added. Epidemiological and economic variables specific for each country were used, and it was assumed that pneumococcal and influenza vaccines would both be administered during the same physician visit. In the base-case analyses, the cost-effectiveness ratios ranged from euro 9239 to euro 23,657 per quality-adjusted life-year. Because the incidence and mortality of invasive pneumococcal disease were underestimated in most countries, a country-by-country analysis was performed, assuming an incidence of 50 cases per 100,000 population and mortality rates of 20, 30 and 40%. For a mortality of 20%, the cost-effectiveness ratios ranged from euro 4,778 to euro 17,093, and for a mortality of 30%, they ranged from euro 3,186 to euro 11,395. Pneumococcal vaccination to prevent invasive pneumococcal disease in elderly adults was very cost-effective in all 10 countries. This evidence justifies the wider use of the vaccine in Western Europe.

Molecular epidemiology of penicillin-non-susceptible Streptococcus pneumoniae isolates from children with invasive pneumococcal disease in Germany.

A population-based nationwide surveillance of antibiotic resistance associated with invasive pneumococcal disease (IPD) in children and adolescents (aged<16 years) was performed in Germany between 1997 and 2004. In total, 1517 isolates were collected, of which 5.1% and 1.1% were intermediately- or fully-resistant, respectively, to penicillin G. During the 8-year study period, an increase in resistance to both penicillin G and erythromycin A was observed, and the frequency of isolates exhibiting reduced susceptibility to penicillin G or erythromycin A increased from 1.4% and 11.1%, respectively, in 1997, to 8.7% and 29.0%, respectively, in 2004. Among the penicillin non-susceptible pneumococcal isolates, serotypes 14 (24.5% of isolates), 23F (16.0%) and 6B (16.0%) were found most frequently. Multilocus sequence typing of 58 (62%) penicillin G non-susceptible isolates revealed that sequence type (ST) 156 (Spain9V-3 clone) and its single-locus variant ST 557 were widespread in Germany. Moreover, 17 new penicillin G non-susceptible STs were defined for the first time. The study illustrated the genetic heterogeneity of antibiotic-resistant pneumococcal isolates in Germany.

Globicatella sanguinis is an etiological agent of ventriculoperitoneal shunt-associated meningitis.

Globicatella sanguinis is a very rare isolate in clinical samples. We present a case of meningitis in a 69-year-old female patient after implantation of an external left ventricular drainage due to a hydrocephalus. She recovered after antibiotic treatment with ceftriaxone.

[Medical indications and effectiveness of the pneumococcal conjugate vaccine]. / Indikationen und Nutzen der Pneumokokken-Konjugat-Vakzine.

Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, sinusitis, and acute otitis media in children and adults worldwide. Especially in the age group of < 2 years the incidence of invasive pneumococcal is high. The vulnerability of children to S. pneumoniae can also be demonstrated by the high rate of sequelae (> 20 % in Germany) and the high mortality (7.5 %) in pneumococcal meningitis. A 7-valent pneumococcal conjugate vaccine that was shown to be highly efficacious in preventing invasive pneumococcal disease in infants in the USA was licensed in Europe in 2001. It is expected that broad usage of the vaccine would reduce the incidence of invasive pneumococcal disease and the levels of pneumococcal resistance significantly.

Distribution of four capsular serotypes of Enterococcus faecalis among clinical isolates from different geographical origins and infection sites.

BACKGROUND: Enterococci possess capsular polysaccharide antigens that are the targets of opsonic antibodies. These antibodies are potential candidates for development as immunotherapy. MATERIAL AND METHODS: The present study analyzes the distribution of four capsular serotypes within a collection of 157 isolates of Enterococcus faecalis from four countries with different sites of clinical infection. RESULTS: By using a capsular polysaccharide-specific ELISA, 42% of the isolates were grouped into one of four serogroups, and another 9% showed cross-reactivity between two serotype-specific sera. Heterogeneity of serotype distribution by both geographical origin and infection site was observed. CONCLUSION: Half of the strain collection could be typed with four serotype-specific sera. No serotype from a given country or infection site clearly predominated.

Invasive pneumococcal disease in adults in North-Rhine Westphalia, Germany, 2001-2003.

A population-based survey of invasive pneumococcal disease (IPD) was conducted among adults in North-Rhine Westphalia, Germany. The study included 202 of the 386 hospitals in the region, together with the 27 microbiological laboratories that submitted reports of IPD in these hospitals to the National Reference Centre for Streptococci. The reports of 16 laboratories were comprehensively reviewed. Most (95.8%) IPD isolates were susceptible to penicillin G, but 14.5% were resistant to clarithromycin. Serotypes 14 (15.6%), 3 (9.3%), 4 (7.1%) and 7F (7.9%) were the most common. The serotype coverage of the 23-valent pneumococcal polysaccharide vaccine was 80.8%. During 2001-2003, the annual incidence of IPD, after correcting for laboratory and hospital under-reporting, was 16.2/100 000 in individuals aged >or= 65 years. In three university hospitals, blood cultures were obtained for only 37% of patients with community-acquired pneumonia, and fewer than one-third of such cultures were obtained in one hospital before antibiotics were prescribed, suggesting that the true incidence of IPD was closer to 50/100 000.

Global distribution of Streptococcus pneumoniae serotypes isolated from paediatric patients during 1999-2000 and the in vitro efficacy of telithromycin and comparators.

Few data exist on the distribution of Streptococcus pneumoniae serotypes in many countries and in non-invasive disease overall. Here, data are presented from 772 paediatric isolates from children with community-acquired respiratory tract infections isolated from the PROTEKT global surveillance study during 1999-2000. Overall, 60.0 % of isolates were covered by the 7-valent pneumococcal vaccine formulation (PCV7), with greater coverage in the USA compared with Europe (69.6 vs 55.5 %, P = 0.014). Geographically dispersed clones of serogroups 3, 11 and 15 accounted for most of the isolates outside PCV7 coverage. Overall, macrolide, penicillin and cotrimoxazole non-susceptibility rates were high; however, all isolates were susceptible to telithromycin. Although only 7.4 % of isolates were resistant to amoxycillin/clavulanate, a higher prevalence of resistance was found in isolates from the USA and South Korea. This study shows the feasibility and importance of serotyping antibiotic surveillance study isolates and the potential of telithromycin as an important option for empiric therapy.

Antibacterial resistance of community-acquired respiratory tract pathogens recovered from patients in Germany and activity of the Ketolide Telithromycin: results from the PROTEKT surveillance study (1999-2000).

BACKGROUND: The Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT) longitudinal global surveillance study examines the antibacterial susceptibility of community-acquired respiratory pathogens. METHODS AND RESULTS: Data from isolates collected in Germany in 1999-2000 in the PROTEKT study show that 8.3% of pneumococcal isolates (n = 325) had reduced susceptibility to penicillin and 2.2% were fully resistant. Erythromycin resistance was 15.7% overall and particularly high in Leipzig (31.6%). All penicillin- and erythromycin-resistant strains were inhibited by telithromycin (MIC < or =0.5 mg/l) and linezolid (MIC < or =2 mg/l). Beta-lactamase was produced by 3.2% of Haemophilus influenzae (9/284) and 89.5% of Moraxella catarrhalis strains (111/124). All Streptococcus pyogenes isolates (n = 87) were susceptible to penicillin, although 9.2% were resistant to macrolides. CONCLUSIONS: Penicillin resistance in Germany remains low; however, the prevalence of antimicrobial resistance among common respiratory pathogens is rising, particularly against macrolides. Continued surveillance is necessary to guide optimal empirical therapy, and new antimicrobials, like telithromycin, need to be developed with improved potency against target pathogens and low propensity for the development of resistance.