Prospective surveillance of incidence, serotypes and antimicrobial susceptibility of invasive Streptococcus pneumoniae among hospitalized children in Austria

Pamela Rendi-Wagner1, Apostolos Georgopoulos2,*, Michael Kundi3, Ingomar Mutz4, Markus Mattauch5, Jacek Nowak5, Andrea Mikolasek1, Andreas Vecsei6 and Herwig Kollaritsch1

1 Department of Specific Prophylaxis and Tropical Medicine, Institute of Pathophysiology, Medical University Vienna, Kinderspitalgasse 15, A-1095 Vienna; 2 University Clinic for Internal Medicine I, Clinical Department for Infectious Diseases and Chemotherapy, Medical University Vienna, Währinger Gürtel 18–20, A-1090 Vienna; 3 Institute of Environmental Health, Medical University Vienna; 4 Children’s Hospital Leoben, Leoben; 5 Wyeth Lederle Pharma GmbH, Vienna; 6 St Anna Children’s Hospital, Vienna, Austria

Received 19 November 2003; returned 30 December 2003; revised 16 February 2004; accepted 28 February 2004


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives: This study was undertaken to analyse incidence rates, serotype distribution and antimicrobial resistance patterns of invasive Streptococcus pneumoniae isolates from hospitalized children up to 5 years of age with invasive pneumococcal disease (IPD), including meningitis, in Austria.

Methods: From February 2001–January 2003, nationwide prospective surveillance was conducted that included all paediatric hospitals and clinical microbiological laboratories. All invasive pneumococci isolated were serotyped and tested for antimicrobial susceptibility.

Results: The mean annual incidence rates of IPD per 10 000 population for the age groups <24 months and <60 months were 14.5 (7.7 for meningitis) and 13.7 (6.0 for meningitis), respectively. The case fatality rate was 6% for IPD and 12% for meningitis. Of all IPD cases, 69.6% (73.1% for meningitis) were covered by serotypes and 83.9% (88.5% for meningitis) by cross-protection of vaccine-related serotypes. Intermediate penicillin G susceptibility (MIC 0.12–1 mg/L) was found in 12/56 strains. No penicillin G-resistant strains were found. A total of 19/56 isolates showed decreased susceptibility to macrolide agents (MIC >= 1 mg/L).

Conclusions: The IPD incidence rate was similar, and serotype coverage of the 7-valent conjugated vaccine marginally superior, to Germany. The surprisingly high level of antimicrobial resistance among invasive isolates considerably amplifies the potential impact of a childhood pneumococcal vaccination programme in Austria.

Keywords: S. pneumoniae, incidence, serotype coverage, susceptibilities


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Prevention of serious disease and death caused by Streptococcus pneumoniae is considered a high public health priority, particularly in young children and the elderly. Pneumococci are a major cause of otitis media, pneumonia and invasive bacterial infections in early infancy.13 Population-based studies, however, have demonstrated wide geographic and temporal variation in the incidence of invasive pneumococcal disease (IPD), as well as serotype distribution.4 Possible factors responsible for these apparent differences include variability in blood culture rates, antimicrobial resistance levels, ethnic origin, methods of surveillance and identification of cases.57

Despite progress in antimicrobial therapy, effective treatment is becoming increasingly complicated due to the worldwide rising emergence of pneumococci resistant to penicillin G and other commonly used antimicrobial agents.8,9 To date, Austria has had lower rates of resistance compared with other countries such as France, Spain and an increasing number of Central European countries, many of them in geographical proximity to Austria.1012 Undoubtedly, the potential spread of resistant clones from country to country poses a serious cause for concern.13

A heptavalent pneumococcal conjugate vaccine (7-vPc), comprising the pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F and 23F, has recently become available in Austria for use in children under 2 years old. Several studies have indicated that the 7-vPc vaccine is immunogenic, safe and highly effective against invasive disease caused by serotypes contained in the vaccine.1418 It is also partly effective against invasive disease caused by vaccine-related serotypes, as observed by Eskola et al.16 in a clinical trial evaluating 7-vPc-efficacy against otitis media, as well as by large-scale population-based data.17

Knowledge of the regional distribution of pneumococcal capsular types, as well as precise incidence rates, is essential for the development of effective strategies and for the evaluation of their impact on the epidemiology of invasive and non-invasive pneumococcal infections. In addition, well established surveillance tools are needed to monitor changing incidence rates and antimicrobial resistance over time for future calculation of conjugate vaccine efficacy.19 In the near future, a 9-valent vaccine containing the additional serotypes 1 and 5, and an 11-valent vaccine containing the additional serotypes 1, 3, 5 and 7, may be introduced in Austria. The objective of the present study was to obtain information on the incidence of IPD in hospitalized children up to 5 years of age and to evaluate the serotype distribution and local antimicrobial resistance patterns of S. pneumoniae in the above group in the pre-vaccine era in Austria.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study design

The study was based on a 2 year prospective active surveillance of IPD in hospitalized Austrian children up to the age of 5 years, inclusive. The observation period was 1 February 2001–31 January 2003. The annual birth rate in Austria is ~80 000 with a decreasing trend. A total of 30 microbiology laboratories covering 41 children’s hospitals and wards throughout Austria (100% of paediatric hospital beds) participated in this trial.

Cases were eligible for evaluation if they had been admitted to a paediatric hospital and if S. pneumoniae was identified by culture, PCR, or a latex agglutination test of blood, CSF, or any other normally sterile site. Case identification was based on two independent surveillance systems—one hospital-based and the other laboratory-based—by means of per-case questionnaires, which were dispensed at the beginning of each year. The reporting physicians were requested to provide the following patient data to the central study notification centre at the Department of Specific Prophylaxis and Tropical Medicine, University Vienna: age, gender, site of infection, date of hospitalization, clinical diagnosis, date of blood and/or CSF culture taken, pneumococcal vaccination status, attendance at day-care centres (DCC), clinical symptoms, onset of symptoms, antimicrobial treatment before culture and disease outcome. If an isolate from a normally sterile body site had been identified as S. pneumoniae by a local laboratory, the microbiologists were asked to send it to the central study laboratory (Department of Infection and Chemotherapy, University of Vienna).

Cases where S. pneumoniae was isolated from CSF were categorized as ‘meningitis cases’ regardless of the presence of other positive cultures. Cases where S. pneumoniae was isolated from other body sites were categorized as ‘non-meningitis cases’. At the central study notification centre, all case reports from hospital surveillance and laboratory surveillance were linked on the basis of the patients’ initials, year/month of birth, gender, date of sampling and hospital of admission. Collaborating sites were contacted by the central study centre at monthly intervals. Following case notification, the corresponding laboratory/paediatrician was immediately asked to complete reporting in order to reach a 100% correlation between the two surveillance systems. In the present study, cases were only eligible for analysis if the case has been confirmed by both the laboratory and the corresponding paediatrician. In addition, each site was visited once a year.

Microbiological investigations

All participating microbiology laboratories were invited to send pneumococci isolated from a normally sterile body site to the central study laboratory, where the samples were re-cultured (in order to confirm the identity), and where serotyping and susceptibility testing were undertaken. Isolates were identified as S. pneumoniae by optochin sensitivity, bile solubility and PCR amplification of the LytA gene. Capsular typing was carried out by the quellung reaction, using group and factor sera provided by the Statens Serum Institut (Copenhagen, Denmark). Resistance to antibiotics was examined for penicillin G, amoxicillin, co-amoxiclav, clarithromycin, erythromycin A, ceftriaxone and cefpodoxime, by determination of MICs using the broth microdilution method according to NCCLS criteria.20,21

Statistical analysis

Annual incidence rates were based on the number of children of the respective age group at risk during the surveillance period. This number was calculated from annual births and deaths obtained from Statistics Austria.22 The number of births in January 2003 was calculated by extrapolation from births in January during the past 5 years.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Overall incidence

A total of 77 cases of IPD (males: 68%; females: 32%), including 34 cases of meningitis, in children up to the age of 5 years were reported during February 2001–January 2003; 31 were notified in the first year and 46 in the second year of observation. Most cases were observed during February–April and October–November. The mean annual incidence was 13.7 per 100 000 population for IPD and 6.0 per 100 000 population for pneumococcal meningitis. The age-specific incidence rates showed a higher attack rate in children aged <24 months for both IPD (14.5 per 100 000 population per year) and pneumococcal meningitis (7.7 cases per 100 000 population per year) than in children aged 24 to <60 months, where the incidence rate was 7.8 for IPD and 2.4 per 100 000 per year for meningitis (Table 1). The male-to-female ratio was 2.08.


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Table 1. Age-specific annual incidence rates of IPD and pneumococcal meningitis in Austrian children, 2001–2003
 
Of all reported IPD cases, five children died—four of meningitis [case fatality rate (CFR) 11.8%] and one from pneumococcal bacteraemia (CFR 2.3%). On the day of hospital discharge, nine (26%) of the meningitis patients had serious sequelae, whereas such outcomes were seen in only two (5%) of non-meningitis cases. The sequelae included hearing loss (2), hemiparesis (1), hygroma (3), fibrothorax (2) and hydrocephalus (2).

Attendance at community institutions such as DCC was reported in 13% of all IPD cases. In 25% of cases, antibiotics had been prescribed prior to sample taking.

Serotype distribution of isolates from IPD

72.7% of the pneumococci isolated from IPD were sent to the central study laboratory where they were confirmed as S. pneumoniae and serotyped. Twenty-one different capsular serotypes were identified (Figure 1). The 10 most common were 14 (41%), 23F (9%), 6B (7%), 18C (7%), 1 (4%), 9A (4%), 19F (4%), 3 (2%), 4 (2%) and 6A (2%), accounting for 82% of IPD isolates and 85% of cases of meningitis. Of the isolates from IPD, 69.6% were covered by serotypes included in the 7-vPc and 83.9% by vaccine-related serotypes (serogroups). The proportion of pneumococcal meningitis cases covered by the 7-vPc serotypes was 73.1%, with 88.5% covered by vaccine-related serotypes (Figure 1). The coverage rate of IPD cases varied by age: the lowest 7vPc-coverage rate was observed in children <6 months of age (57%), whereas the proportion of potentially preventable cases was highest in the age group 12–24 months (75%).



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Figure 1. Frequencies of pneumoccal serotypes isolated from paediatric IPD cases in Austria, 2001–2003. Grey bars, 7-vPc serotypes; striped bars, vaccine-related serotypes.

 
Four of the five isolates from patients who died could be serotyped; three were serotype 14 and one belonged to serotype 3. Thus three of four isolates from cases of fatal meningitis were covered by 7-vPc serotypes.

The proportion of IPD cases covered by the 9-, and 11-valent pneumococcal conjugate vaccines for all IPD cases was 73.2% (73.1% for meningitis cases) and 75% (76.9% for meningitis cases), respectively. Serotype 1 accounted for the 3.6% increase in coverage from the 7- to the 9-valent vaccine.

Antimicrobial resistance

Antibiotic susceptibility testing of the referred isolates showed that 12 (21.4%) had intermediate resistance to penicillin (MICs 0.12–1 mg/L) (Table 2); isolates fully resistant to penicillin (MIC >= 2 mg/L) were not seen. The majority of the penicillin-intermediate isolates comprised serotypes 14 (41.6%) or 6B (33.3%). Erythromycin A resistance (MICs >= 1 mg/L) was found in 19 (33.9%) isolates, with serotypes 6B and 14 accounting for 73.7% (6B: 21.1%; 14: 52.6%) of them. Similarly, 19 (33.9%) isolates were found to have decreased susceptibility to clarithromycin, with one (1.8%) showing intermediate resistance (MIC 0.5 mg/L) and 18 (32.1%) showing full resistance (MIC >= 1 mg/L). A total of seven (12.5%) (MICs >= 2 mg/L) and three (5.4%) (MICs 1 mg/L) isolates were resistant to cefpodoxime. Ceftriaxone (1.8% resistant; MICs >= 2 mg/L) and amoxicillin (all strains susceptible; MICs <= 2 mg/L) exhibited good activity against IPD isolates.


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Table 2. Antibiotic resistance of Streptococcus pneumoniae isolates from children with IPD in Austria, 2001–2003
 
Of the 12 isolates showing decreased susceptibility to penicillin G, eight exhibited reduced sensitivity to macrolides and 10 were resistant to cefpodoxime (predominantly serotype 14). All macrolide-resistant isolates were cross-resistant to ß-lactams.

Analysing serotype vaccine coverage, hypothetically 75% of penicillin G-intermediate resistant and 73.7% of macrolide-resistant strains would have been covered by the 7-vPc vaccine. The covered proportion of multiple-resistant pneumococci would be 71% .


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Using a comprehensive surveillance system, we have investigated the epidemiology of IPD among Austrian hospital inpatients up to 5 years of age. This study represents the first systematic investigation of this kind in Austria. During the study period, the mean annual incidence of IPD was 14 per 100 000 population, which is comparable to that found in the rest of Europe except Finland, but lower than that reported from the USA and Canada.2328 The rates of pneumococcal meningitis among children <5 years in the present study (six per 10 000) were equal to reports from North America and Finland, indicating that we detected cases at the more severe end of the clinical spectrum.

It may be speculated that the incidence rate for IPD calculated from the present surveillance data constitutes an underestimate since case detection was restricted to hospitalized cases, and also many children may have been treated with antimicrobials before hospital admission, resulting in negative blood cultures. Indeed, in the present study a quarter of all reported cases had received antibiotics prior to sample taking, indicating a considerable rate of empirical antibiotic treatment of febrile conditions in Austria.

IPD studies in North America have reported less severe outpatient bacteraemia more frequently.4,28 Since reliable continuous surveillance of invasive and non-invasive pneumococcal disease proved to be difficult, we, like most other European investigators, based surveillance on incidence trends of hospitalized IPD cases, rather than outpatients. As repeatedly discussed, a confounding factor may be differences in local blood culturing practices, since similar incidence data for IPD cases have been reported from Germany and Switzerland, where diagnostic practices are similar to those of Austria.4,25,29

Consistent with other IPD surveillance data,2325 the mean annual incidence of invasive infections was highest among children <2 years old (15 cases per 100 000 population). Moreover, this age group is more prone to suffer from meningitis than older children. However, the proportion of cases <2 years was lower than that reported from other countries, indicating a lower exposure to S. pneumoniae (e.g. via attendance at DCC, which was reported in only 16% of our cases). As described by others23,24,27 we observed a typical biphasic seasonal pattern, with an autumn rise of incidence followed by a drop in midwinter and a second rise in late winter. It is speculated that the early autumn rise may be associated with the beginning of school, which may well provide the opportunity for exchange of strains of different serotypes between children.30

The case-fatality rate calculated here was similar to that in Germany,25 being highest in patients with meningitis (12%). Serious sequelae, likewise, were mainly a consequence of meningitis (26%). Since no long-term follow-up is available, the prognosis and percentage of resolution of sequelae is not known in about a third of the reported meningitis cases.

The Austrian data promise a somewhat better coverage rate by the 7-vPc vaccine than observed in neighbouring countries.25 Although we lack definitive proof, several lines of evidence suggest cross-protection by vaccine-related serotypes, as seen by Eskola et al.16 in a clinical trial evaluating the vaccine’s efficacy against otitis media and also in a population-based survey in the USA.17 However, it seems that the actual vaccine coverage rate may be somewhere between serotype- and serogroup-specific coverage levels.

Presuming that the same efficacy can be demonstrated by the 9- and 11-valent conjugate vaccines, the IPD coverage rate should increase only marginally (by 3%–5%).31 The high rate of antimicrobial resistance among pneumococci from children with IPD in Austria was an unexpected finding in the present study. Previously, Austria had not been considered a high-risk country in terms of antimicrobial resistance in S. pneumoniae.10,11 The rising prevalence of resistance, not only to penicillin G but also to other commonly used antimicrobials, has been reported only recently.32 However, the present study constitutes the first survey in Austria investigating antimicrobial resistance among invasive S. pneumoniae from children. The rate of intermediate penicillin G resistance in pneumococci, as documented by the present study, is significantly higher than that reported recently in Germany.25 However, penicillin G-resistant strains appear to be extremely rare, as confirmed by the present findings. Similarly, we observed double the macrolide resistance rate of Germany,25,33 which most probably reflects the high rate of macrolide consumption (34% of all oral antibiotics) in Austria in recent years.34 In addition, a high level of cross-resistance was observed, mainly between ß-lactams and macrolides, primarily associated with serotypes 14 and 6B. However, when interpreting these data, one needs to consider that a limitation of this investigation is the low number of isolates tested. Nevertheless, it appears exceedingly important to raise awareness and strengthen these data by continuing surveillance.

When analysing the S. pneumoniae disease burden in order to guide the national vaccination policy, coverage and incidence rates are one of the key but not sole aspects of importance. There is evidence suggesting that the use of conjugate vaccines will reduce the need for antibiotics and the subsequent spread of antimicrobial-resistant pneumococci. Above all, one must not forget that the prognosis for meningitis caused by S. pneumoniae is far worse than the outcome of any other bacterial meningitis in childhood.35,36

In summary, while the Austrian IPD incidence rate is equivalent to that seen in Germany, the 7-valent vaccine coverage rate seems to be marginally higher. The increasingly high level of antimicrobial resistance among invasive isolates considerably amplifies the potential impact of a childhood pneumococcal vaccination programme in Austria.


    Acknowledgements
 
We thank the following paediatricians and microbiologists (including their co-workers) who provided the clinical data and pneumococcal strains: W. Maurer, M. Fink, J. Sommer, I. Goedl, H. Steger, G. Schober, G. Tucek, G. Wewalka, F. Asboth, H. Reckendorfer, D. Kosak, M. Hirschl, A. Schmid (Vienna); F. Paky, E. Hauser, S. Naude (Moedling); H. Salzer (Tulln); P. Schabasser, H. Koerbl (Mistelbach); R. Bruckner, H. Hudler (Wr.Neustadt); H. Eggenbauer (Zwettl); A. Herzog, R. Svetitsch, W. Oehlinger (Krems); K. Zwieauer, E. Schuster, C. Aspoeck, E. Unfried (St. Poelten); F. Baumgartner (Stolzalpe); R. Moser, K. Prein (Leoben); W. Zenz, H. Grubbauer, S. Heuberger, A. Bogiatzis (Graz); J. Riedler, M. Bender (Salzburg); H. Haas, A. Hittmaier (Schwarzach); T. Wanka (Braunau); E. Siegl, E. Ziegler, W. Pammer (Wels); U. Roider, P. Eistenhuber, K. Fuchs (Voecklabruck); M. Meissl (Schaerding); M. Raml (Grieskirchen); I. Ettinger (Kirchdorf/Krems); K. Schmitt, G. Zauner, M. Drlicek, L. Binder (Linz); J. Emhofer, J. Feichtinger (Steyr); U. Deinsberger, E. Grund (Klagenfurt); B. Eichwalder, G. Schaller, B. Schwegel, H. Tomantschger (Villach); R. Reindl (Bludenz); B. Ausserer, J. Wohlgenannt (Dornbirn); C. Huemer (Bregenz); B. Simma, U. Gruber, G. Hartmann (Feldkirch); B. Covi, F. Allerberger (Innsbruck); J. Kersak (Zams); M. Schwaiger (St. Johann); F. Mueller (Lienz); K. Loranth, E. Krutisch (Eisenstadt); W. Mueller (Reutte-Ehenbichl); K. Toth, H. Kaiser (Oberwart); G. Loesch (Horn). Moreover, we thank Karin Stich (MTA) and Waltraud Schmidt (MTA) for their skilful technical assistance. The study was supported by Wyeth Lederle Pharma GmbH.


    Footnotes
 
* Corresponding author. Tel: +43-1-40400-5139, Fax: +43-1-40400-5200; E-mail: apostolos.georgopoulos{at}meduniwien.ac.at Back


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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