JOURNAL OF CLINICAL MICROBIOLOGY, June 2006, p. 2032–2038 0095-1137/06/$08.00⫹0 doi:10.1128/JCM.00275-06Copyright 2006, American Society for Microbiology. All Rights Reserved.
Distribution and Invasiveness of Streptococcus pneumoniae Serotypes in Switzerland, a Country with Low Antibiotic Selection Pressure, from 2001 to 2004 Andreas Kronenberg,1 Phillip Zucs,2 Sara Droz,1 and Kathrin Mu Institute for Infectious Diseases, University Bern, CH-3010 Bern, Switzerland1; Federal Office of Public Health, Bern, Switzerland2; and Department for Infectious Diseases, University Hospital Bern, Bern, Switzerland3 Received 8 February 2006/Returned for modification 17 March 2006/Accepted 27 March 2006 To describe the serotype-specific epidemiology of colonizing and invasive Streptococcus pneumoniae isolates,
which is important for vaccination strategies, we analyzed a total of 2,388 invasive and 1,540 colonizing S.
isolates collected between January 2001 and December 2004 within two nationwide surveillance
programs. We found that the relative rank orders of the most frequent serotypes (serotypes 1, 3, 4, 6B, 7F, 14,

19F, and 23F) differed among invasive and colonizing isolates. Serotypes 1, 4, 5, 7F, 8, 9V, and 14 had increased
invasive potential, and serotypes/serogroups 3, 6A, 7, 10, 11, 19F, and 23F were associated with colonization.
The proportion of pediatric serotypes was higher among children <5 years old (48.5%) and persons >64 years
old (34.1%) than among other age groups (29.1%); it was also higher in West Switzerland (40.2%) than in other
geographic regions (34.7%). Likewise, serotype-specific proportions of penicillin-resistant isolates for types 6B,
9V, 14, and 19F were significantly higher in West Switzerland. The relative frequency of pediatric serotypes

corresponded with antibiotic consumption patterns. We conclude that the epidemiology of invasive and
colonizing S. pneumoniae
isolates is influenced by the serotype-specific potential for invasiveness, and therefore,
surveillance programs should include colonizing and invasive S. pneumoniae
isolates. Antibiotic selection
pressure determines the serotype distribution in different age groups and geographic regions and therefore the
expected direct and indirect effects of the 7-valent conjugate vaccine.

Streptococcus pneumoniae is a common cause of severe in- pneumococcal resistance (6). This approach assumes that the vasive disease and upper respiratory tract infections. For ex- serotype-specific epidemiology of invasive and colonizing ample, the annual incidence of otitis media in Switzerland is pneumococci is largely comparable or at least correlated in a 22,500/100,000 children ⬍2 years of age and 18,000/100,000 predictable manner. Few studies have compared the serotype children between 2 and 5 years of age (9). The virulence of S. distribution and antibiotic resistance prevalence of invasive pneumoniae is largely determined by its polysaccharide cap- and nasopharyngeal pneumococci (20, 21, 24, 26, 27). More sule, which is also the target of pneumococcal vaccines in recently, several studies have estimated the invasiveness of current use. More than 90 serotypes have been identified based prevalent pneumococcal serotypes based on the relative sero- on the antigenic composition of the polysaccharide capsule.
type prevalence in invasive and colonizing isolates (1, 14, 28).
Some of these serotypes exhibit a distinctive epidemiology with Low numbers of pneumococcal isolates and/or a limited com- regard to their potential to cause invasive disease, their occur- parability of study groups from which invasive and noninvasive rence in specific age groups or geographic regions, their asso- S. pneumoniae isolates were collected hampered a detailed ciation with antibiotic resistance, and their epidemic potential analysis in many of these studies.
This study made use of two nationwide Swiss surveillance The introduction of the 7-valent conjugated pneumococcal systems, one monitoring nasopharyngeal pneumococcal car- polysaccharide vaccine (PCV-7; serotypes 4, 6B, 9V, 14, 18C, riage and the other focusing on invasive pneumococcal disease.
19F, and 23F) stresses the importance of surveillance of pneu- Invasive and colonizing S. pneumoniae isolates collected pro- mococcal serotype-specific epidemiology. Replacement of vac- spectively between January 2001 and December 2004 were cine serotypes with nonvaccine serotypes has been observed in compared with regard to their relative serotype distribution several vaccine studies and also shortly after the introduction and antibiotic resistance prevalence. In addition, the relative of universal vaccination of infants in the United States (16, 32).
invasiveness of pneumococcal serotypes was estimated as de- A precise estimation of the prevalence of drug-resistant in- scribed previously by Brueggemann et al. (1, 2).
vasive S. pneumoniae isolates is hampered by the relatively low (Part of the data was presented at the Annual Assembly of numbers of cases in young age groups. Therefore, in 1996, the the Swiss Society for Infectious Diseases, Basel, Switzerland, Centers for Disease Control and Prevention recommended June 2005, and the Meningitis Research Foundation Confer- that nasopharyngeal isolates be used for the surveillance of ence, London, United Kingdom, November 2005.) MATERIALS AND METHODS
* Corresponding author. Mailing address: Institute for Infectious Diseases, University of Bern, Friedbu ¨hlstrasse 51, 3010 Bern, Switzer- Invasive and colonizing pneumococcal isolates. Data on invasive S. pneu-
land. Phone: 41 31 632 32 59. Fax: 41 31 632 87 66. E-mail: kathrin moniae were obtained from the Swiss National Reference Center for Invasive Pneumococci (NRCP). Reporting of invasive pneumococcal infection has been SEROTYPE-SPECIFIC EPIDEMIOLOGY OF S. PNEUMONIAE mandatory in Switzerland since 1999 ( In March 2002, TABLE 1. Characteristics of 2,388 invasive pneumococcal isolates the NRCP ( was set up and has since been prospectively from the Swiss National Reference Center (March 2002 to collecting clinical pneumococcal isolates from normally sterile body sites (blood, December 2004) and 1,540 pneumococcal nasopharyngeal cerebrospinal fluid, and joint, pleural, and peritoneal fluid but not middle-ear isolates from the Swiss Sentinel Surveillance Network fluid) sent by Swiss clinical microbiology laboratories. The referral of invasive (January 2001 to December 2004) pneumococcal isolates to the NRCP is voluntary. Nevertheless, it is estimatedthat the center receives ⬎95% of all invasive isolates cultured in Switzerland. For No. (%) of pneumococcal instance, the number of invasive infections reported to the Swiss Federal Office of Public Health during the years 2003 and 2004 was 924 and 1,000, respectively.
During the same time, the NRCP received 901 and 968 isolates, respectively. Inthis study, data on invasive isolates from March 2002 to December 2004 were 2,388 (100) 1,540 (100) Data on colonizing pneumococci were obtained from the Pneumococcal Re- sistance Study that is being conducted within the Swiss Sentinel System. This 972 (63.3) ⬍0.001 nationwide, ongoing, prospective pneumococcal surveillance study has been de- scribed in detail previously (25). In brief, nasopharyngeal swabs are collected from all outpatients who present with acute otitis media or pneumonia to prac- titioners participating in the sentinel network. S. pneumoniae is being cultured 735 (48.0) ⬍0.001 from the swabs at the Institute for Infectious Diseases, University of Bern, Bern, Switzerland, as previously described (25). In this study, data for nasopharyngeal Penicillin (MIC ⬎ 0.06 mg/liter) isolates from January 2001 to December 2004 were included.
Penicillin (MIC ⬎ 2 mg/liter) Serotyping and resistance testing were done for all invasive and colonizing bacterial isolates included in this study at the Institute for Infectious Diseases, University of Bern, Switzerland, as previously described for the colonizing iso- lates (25). In brief, capsular serotyping was done on all isolates by a Quellung reaction using antiserum from the Statens Serum Institute (Copenhagen, Den- mark). All isolates were tested against oxacillin (1-␮g disk), erythromycin, cotri- moxazole, and levofloxacin by the disk diffusion method. For isolates with re- duced susceptibility to any of these four antibiotics, MICs were determined by use of the E test method (AB Biodisk) according to Clinical and Laboratory Standards Institute (CLSI) (formerly NCCLS) guidelines (7). Data on patients' age and gender were available for invasive and colonizing isolates, whereas patients' canton (state) of residence was derived from the sending laboratory's or sentinel physician's address. Also, for invasive isolates, the anatomical site of isolation was known.
Antibiotic consumption data. Data on outpatient antibiotic sales were pro-
vided by IMH-IMS Health Market Research and have partially been published previously (11). Defined daily doses (DDD) per 1,000 inhabitants daily were calculated using WHO standard doses and demographic information from the last census in 2000.
Statistical analysis. Serotype distribution was analyzed for invasive and colo-
nizing isolates by age group and geographic region. For the purpose of geo- graphic comparisons, Switzerland was divided into two regions, the French- speaking West and the remaining parts of the country (designated "other"), as 252 (16.4) ⬍0.001 described previously (25).
Serotype/serogroup-specific penicillin resistance was calculated as the propor- tion of penicillin-nonsusceptible S. pneumoniae (PNSP) isolates in each serotype/ An odds ratio (OR) was calculated for the likelihood of an individual serotype/ serogroup being isolated from a sterile site compared to merely colonizing a a NS, not significant (P ⬎ 0.05).
patient, as described previously (1). For the main analysis, all other serotypes/ b Numbers for serogroups 6, 7, 9, and 23 do not include serotypes 6B, 7F, 9V, serogroups served as the reference group. For comparison with the literature, the analysis was repeated with serotype 14 as a fixed reference (2). Age and geo-graphic region were added to the model as potential confounders.
Descriptive analysis, analysis of variance, and logistic regression analysis were performed using StatView (version 5.0; SAS Institute). Proportions were com- and geographic provenance: colonizing isolates were cultured pared with the chi-square or Fisher's exact test as appropriate. A cutoff P value more often from children ⬍5 years of age and were from the of ⱕ0.05 (two-tailed) was used for all statistical analyses.
Western part of Switzerland (Table 1). These potentially con-founding variables were taken into account in the multivariate Serotype/serogroup distribution among invasive and colo-
A total of 2,388 invasive S. pneumoniae isolates collected by nizing isolates. Capsular serotyping of isolates yielded 41 dif-
the NRCP between March 2002 and December 2004 were ferent serotypes/serogroups. A small percentage of isolates analyzed. Invasive isolates were obtained mainly from blood (3.1%) were nontypeable. With the exception of serotypes 5 cultures (90.8%) or cerebrospinal fluid (3.5%). In addition, the and 6A, serotypes/serogroups that accounted for ⬍1% of all study included data on 1,540 nasopharyngeal pneumococcal isolates were combined into a group designated "other" for isolates collected between January 2001 and December 2004 further analyses (Table 1). Serotype/serogroup distribution dif- within the Swiss Sentinel Surveillance Network, designated as fered between invasive and colonizing isolates (Table 1). In the colonizing S. pneumoniae isolates. Invasive and colonizing univariate analysis, serotypes/serogroups 1, 4, 7F, 8, 9V, 14, study isolates showed different distributions for patients' age and 22 occurred significantly more often among invasive iso- KRONENBERG ET AL.
However, the observed trends confirmed the findings of theoverall analysis (data not shown).
Serotype/serogroup distribution by age and geographic re-
gion. The serotype distribution did not differ significantly be-
tween the age groups 0 to 1 and 2 to 4 years and between the
age groups 5 to 16 and 17 to 64 years (data not shown), which
were therefore pooled for further analysis. Figure 2 illustrates
the distribution of serotypes/serogroups by age group and geo-
graphic region. The following associations were confirmed by
multivariate analysis, adjusting for geographic region or age
group (as appropriate) and colonizing versus invasive isolates
(data not shown): (i) serotypes/serogroups 6 (P ⫽ 0.009), 6B
FIG. 1. ORs and 95% confidence intervals for the probability of S. ⬍ 0.001), 14 (P ⫽ 0.008), 15 (P ⫽ 0.003), 19F (P ⬍ 0.001), and pneumoniae being isolated from a normally sterile site compared to 23F (P ⬍ 0.001) were most common among young children ⬍5 being isolated from the nasopharynx for different serotypes/serogroups years of age; (ii) serotypes/serogroups 1 (P ⬍ 0.001), 3 (P ⬍ adjusted for age and geographic region. The numbers in parentheses 0.001), 7 (P ⫽ 0.01), 7F (P ⫽ 0.05), 8 (P ⫽ 0.001), 9 (P ⫽ 0.04), next to the serotypes/serogroups on the x axis indicate the number of and 22 (P ⫽ 0.001) were more frequent among older children and adults; and (iii) serotypes/serogroups 9 (P ⫽ 0.05) and 19A(P ⫽ 0.02) prevailed in the western part of Switzerland, whileserotypes 3 (P ⫽ 0.04) and 7F (P ⫽ 0.03) were more frequent lates. Serotypes/serogroups 6, 6B, 10, 11, 15, 18C, 19F, and 23 in other areas.
and nontypeable isolates were more frequent among coloniz- Serotype/serogroup and antibiotic resistance. The overall
ing isolates. Among the rare serotypes/serogroups (⬍1% of all proportions of PNSP (MIC ⬎ 0.06 mg/liter) and high-level isolates), serotype 5 was represented by eight (0.3%) invasive penicillin (MIC ⱖ 2 mg/liter), erythromycin, cotrimoxazole, isolates and one (0.1%) colonizing isolate (P ⬎ 0.05), serotype and levofloxacin resistance were 12.1%, 1.0%, 13.2%, 18.9%, 6A was found only among colonizing isolates (0.4%, P ⫽ and 0.7%, respectively.
0.004), serotype 12F occurred only among invasive isolates PNSP isolates were significantly more frequent among col- (0.7%, P ⬍ 0.001), and serotype 38 was less frequent among onizing isolates, while high-level resistance to levofloxacin and invasive isolates (0.1%) than among colonizing isolates (0.6%) penicillin was more frequent among invasive isolates. These (P ⫽ 0.002).
differences remained significant for high-level penicillin resis- Association of serotypes/serogroups with invasiveness. ORs
tance and levofloxacin resistance after adjustment for age and were calculated for individual serotypes/serogroups in a logis- geographic region (P ⫽ 0.04 for each antibiotic). Half (48.8%) tic regression model adjusting for age and geographic region of the isolates with high-level penicillin resistance belonged to (Fig. 1). Serotypes 1 (OR, 2.9; 95% confidence interval [CI], serotype 14. Serotype distribution among levofloxacin-resistant 1.8 to 4.7), 4 (OR, 4.7; 95% CI, 2.7 to 8.1), 7F (OR, 6.2; 95% isolates was more diverse (data not shown).
CI, 3.4 to 11.5), 8 (OR, 4.4; 95% CI, 2.2 to 8.7), 9V (OR, 2.4; Serotype-specific PNSP proportions (serotype-specific resis- 95% CI, 1.3 to 4.3), and 14 (OR, 3.0; 95% CI, 2.2 to 4.0) were tance [SSR]) differed between serotypes/serogroups (Table 2).
significantly associated with invasive isolates (Fig. 1). These six PNSP proportions were higher in serotypes/serogroups 5, 6A, serotypes contributed 43.1% of all invasive isolates compared 6B, 9, 9V, 14, 15, 19A, 19F, and 23F and nontypeable isolates.
to 12.9% of all colonizing isolates (P ⬍ 0.001). Serotype 14 was In the univariate analysis, SSR differed significantly between the most prominent invasive serotype, comprising 15.3% of colonizing and invasive S. pneumoniae isolates for serotypes/ invasive isolates, but it also belonged to the more prevalent serogroups 1 (11.5 versus 0%; P ⫽ 0.004), 9 (without 9V, 28.8 colonizing serotypes (7% of all colonizing isolates). Serotypes versus 7.5%; P ⫽ 0.001), and 23F (9.8 versus 20.4%; P ⫽ 0.02).
3 (OR, 0.4; 95% CI, 0.3 to 0.6), 7 (OR, 0.5; 95% CI, 0.3 to After controlling for age and geographic region, 23F remained 0.95), 10 (OR, 0.5; 95% CI, 0.2 to 0.9), 11 (OR, 0.6; 95% CI, the only serotype for which SSR and invasiveness were signif- 0.3 to 0.95), 15 (OR, 0.4; 95% CI, 0.2 to 0.8), 19F (OR, 0.3; icantly associated (adjusted OR, 3.38; 95% CI, 1.34 to 8.55; 95% CI, 0.2 to 0.4), and 23 (OR, 0.4; 95% CI, 0.2 to 0.9) were P ⫽ 0.009). Interestingly, four serotypes with high odds ratios significantly associated with colonizing isolates (Fig. 1). To- for the association with invasiveness (serotypes 1, 4, 7F, and 8) gether, they contributed 42.5% of all colonizing isolates com- belonged to the serotypes with the lowest SSR (Table 2 and pared to 21.4% of all invasive isolates (P ⬍ 0.001).
Fig. 1). However, there was no significant linear correlation be- When the logistic regression analysis of the association of tween the OR for invasiveness and SSR. As illustrated in Fig. 1, individual serotypes/serogroups with invasive and colonizing serotype 3 and serogroup 7, which were more prevalent among isolates was repeated using serotype 14 as a reference in anal- colonizing serotypes, had low SSR, and serotypes 14 and 9V, ogy to the study reported previously by Brueggemann et al. (2), which belong to the "invasive" serotypes, had high SSR.
similar results were obtained. Serotypes 1, 4, 7F, 8, 9V, and SSR did not vary significantly by age group (data not shown).
19A were at least as invasive as serotype 14, whereas all other However, SSR proportions for serotypes 6B, 9V, 14, and 19F serotypes tested were significantly more often associated with and nontypeable isolates were significantly higher in the West colonization than serotype 14.
than in other geographic regions (Table 2). Interestingly, se- Small numbers did not allow for an in-depth analysis of rotypes 6B, 9V, 14, and 19F belong to the five so-called pedi- serotype-specific invasiveness among different age groups.
atric serotypes.
SEROTYPE-SPECIFIC EPIDEMIOLOGY OF S. PNEUMONIAE FIG. 2. Serotype/serogroup distribution of invasive (A and C) and colonizing (B and D) S. pneumoniae isolates by age group and geographic region. The numbers in parentheses next to the serotypes/serogroups on the x axis indicate the number of isolates.
Pediatric serotypes and vaccine coverage. The pediatric se-
rotypes 6B, 9V, 14, 19F, and 23F were found more frequentlyamong children ⬍5 years of age (48.5%) and elderly patients(34.1%) than among patients between 5 and 64 years old TABLE 2. Serotype/serogroup-specific penicillin resistance of (29.1%) (P ⬍ 0.001 for children ⬍5 years old; P ⫽ 0.007 for invasive and colonizing S. pneumoniae isolates by geographic region elderly patients ⬎64 years old) (Table 3). The proportions ofpediatric serotypes did not differ significantly between the age groups 0 to 6 months (43.0%), 7 to 24 months (49.8%), and 25 to 48 months (46.8%). Also, pediatric serotypes did not occur more frequently among women of childbearing age (17 to ⬍45 years old) than among men of the same age group (27.1% versus 28.9%, respectively). There was a trend towards a higher proportion of pediatric serotypes in the Western region The stratified analysis for penicillin-susceptible and PNSP iso- lates showed that the variation of the proportion of pediatric serotypes by age group was seen only among penicillin-susceptible isolates (Table 3). In the Western region, the predominance of pediatric serotypes occurred only among PNSP isolates.
The proportions of invasive (46.2%) and colonizing (48.3%) isolates covered by PCV-7 (excluding potentially cross-reacting serotypes) were relatively low but comparable. The propor- tions were higher among infants ⬍2 years of age (65.1% for invasive and 56.1% for colonizing isolates) and children 2 to 4 years old (51.3% for invasive and 49.9% for colonizing iso- lates). Similar, albeit smaller, variations were found for the proportion of vaccine serotypes in different age groups and geographic regions. This is not unexpected, since five of the seven serotypes included in the vaccine belong to the pediatric P value was adjusted for age group and the proportion of colonizing and invasive isolates. NS, not significant (P ⬎ 0.05).
TABLE 3. Risk factors for pneumococcal carriage or invasive disease have shown no significant differences in the serotype distribu- with pediatric serotypes (6B, 9V, 14, 19F, and 23F) among 3,928 tions between children with acute respiratory tract infection children and adults in Switzerland from 2001 to 2004 and healthy children (1, 14, 30). Due to the design of the two Isolate group and surveillance programs that provided the study isolates, invasive and colonizing isolates differed significantly in their distribu- tion by age and geographical location. However, the large Geographical region number of strains included allowed us to control for potential confounders by multivariate analysis. Previous studies have analyzed the characteristics of individual clones within preva- lent serotypes (1, 14, 28). In this study, the genetic population structure was obtained for only a small fraction of the studyisolates (data not shown), which did not allow for a detailed Penicillin susceptible analysis. However, the serotype/serogroup can still serve as a Geographical region valid unit for analysis of the invasive potential of S. pneu- moniae (16).
This study found a significant association of serotypes/sero- groups 1, 4, 7F, 8, 9V, 12F, and 14 with invasive disease and an association of serotypes/serogroups 3, 6A, 7 (other than 7F),10, 11, 15, 19F, 23 (other than 23F), and 38 with colonization.
Geographical region This corresponds with recent reports from other geographic regions (1, 2, 14, 28). There were some exceptions. Serotype 18C was associated with a higher invasive potential in studies from the United Kingdom, Sweden, and Finland (1, 14, 28), but this association could not be confirmed in this study despite a sufficient number of serotype 18C isolates. Similar to the a Odds ratio was adjusted for age or geographic region (as appropriate) and findings by Brueggemann et al. (1, 2), the rare serotype 38 did anatomical site (colonization versus invasive infection).
Outpatient antibiotic consumption. Antibiotic consumption
was higher in West Switzerland (12.4 to 13.0 DDD per 1,000inhabitants daily) than in the rest of Switzerland (7.9 to 8.5DDD per 1,000 inhabitants daily). In addition, cephalosporinswere used more often in West Switzerland than in the rest ofSwitzerland (10.7 to 11.6% versus 6.8 to 7.1% of total antibi-otic consumption). Total consumption rates as well as therelative distribution of different antibiotic classes were stablebetween 2002 and 2004 (Fig. 3).
The particular strength of this study was the availability of large strain collections from two simultaneous, ongoing, pro-spective, nationwide, and representative pneumococcal sur-veillance programs for invasive and colonizing S. pneumoniaeisolates in combination with national data on antibiotic con-sumption. Previous studies, which compared invasive and col-onizing pneumococcal isolates, were based on smaller straincollections and were restricted to children or children attend-ing day care centers (1, 2, 14, 28). In Switzerland, PCV-7 waslicensed in 2000. Official recommendations were restricted tochildren at risk, and vaccine use has been low (Swiss FederalOffice of Public Health recommendations). Therefore, PCV-7had no influence on the study results.
The present study also has some limitations. Epidemiologi- cal data related to study isolates were scarce, i.e., there was noinformation about comorbidities. Colonizing isolates were ob-tained from the nasopharynx of patients with acute respiratory FIG. 3. Absolute (A) and relative (B) outpatient antibiotic con- tract infection and not from healthy persons. This may have sumption in DDD per 1,000 inhabitants per day in West Switzerland influenced the serotype distribution. However, previous studies compared to the rest of Switzerland from 2002 to 2004.
SEROTYPE-SPECIFIC EPIDEMIOLOGY OF S. PNEUMONIAE not appear to exhibit an increased invasive potential as sug- considerably lower than that reported in previous reports from gested previously by Hanage et al. (14). One likely explanation the United States (⬎44%), Scotland (58%), and Sweden for this discrepancy could be that distinct clones of serotypes (48%) (8, 10, 19, 23). Waning immunity with increasing age, 18C and 38 circulate in Northern Europe. The characterization antibiotic selection pressure, and increased exposure to pedi- of serotypes/serogroups with high invasive potential is of epi- atric serotypes have been discussed as possible explanations for demiological and public health importance. Pneumococcal se- the predominance of pediatric serotypes among the elderly rotypes/serogroups with a propensity for colonization are also population (10). All three factors probably play a role and act relevant since they can cause high morbidity through upper in concert. Here, as in the United States (10), the association respiratory tract infections such as acute otitis media. Surveil- of pediatric serotypes with old age was also preserved when the lance should therefore include both colonizing and invasive analysis was restricted to penicillin-susceptible isolates. This supports the suggested role of waning immunity in the selec- Serotypes 1, 4, 7F, and 8, which have a high risk for inva- tion of pediatric serotypes. However, antibiotic selection pres- siveness, had very low proportions of serotype-specific penicil- sure is also likely to be an important factor. In Switzerland, the lin resistance. Low exposure to antibiotic selection pressure rate of antibiotic consumption in outpatients is among the and reduced probability for the acquisition of resistance genes lowest observed in Europe, with an average of 8.97 DDD per due to a short duration of colonization may explain this asso- 1,000 inhabitants per day (5, 11, 12). Only in The Netherlands ciation. Serotype 3 had little resistance despite a propensity for has antibiotic consumption been equally low. Low antibiotic colonization. A constitutively high level of expression of the selection pressure may explain the relatively low proportion of polysaccharide capsule in serotype 3 may impede invasiveness pediatric serotypes among the elderly population observed in and the acquisition of resistance genes during colonization (13, this study. These findings are relevant for the expected indirect 31). Serotypes 14 and 9V have been associated with both in- effect (herd immunity) of PCV-7 on older age groups and for vasive disease and antibiotic resistance. However, both sero- the potential use of this vaccine in the elderly (10, 32). The types are probably good invaders and colonizers, as described proportion of serotypes covered by PCV-7 among infants was in this study and previous studies (1, 14, 28).
lower in Switzerland than in other European countries (16, 17).
The relative serotype/serogroup distribution differed be- Again, low antibiotic selection pressure seems to be an impor- tween invasive and colonizing S. pneumoniae isolates. Varia- tant reason for this observation. In contrast with previous stud- tions were due mostly to different rank orders of serotypes/ ies from the United States and South Africa, no association serogroups rather than a vastly different composition. The was found between pediatric serotypes and women of child- differences in rank orders reflected the invasive or colonizing bearing age (3, 10). This suggests that sociodemographic fac- potential of individual serotypes/serogroups as described tors associated with low crowding may have also influenced the above. This is in accordance with findings of previous studies study results.
(20, 21, 26). The major discrepancies between colonizing and A higher proportion of pediatric serotypes and significantly invasive pneumococci were related to serotypes 14, which pre- higher serotype-specific proportions of penicillin resistance for dominated among invasive isolates, and 19F, which was the the pediatric serotypes 6B, 9V, 14, and 19F were observed in most frequent colonizing serotype. Since both serotypes were West Switzerland. Antibiotic consumption among outpatients associated with penicillin resistance and since both serotypesare included in the 7-valent conjugated vaccine, neither the in this region is significantly higher than in other regions of overall penicillin resistance nor the proportion of serotypes Switzerland (Fig. 3) (11, 25). In addition, cephalosporins, covered by the vaccine differed significantly between colonizing which exert a higher selection pressure for penicillin-resistant and invasive isolates. However, this balance could easily be S. pneumoniae isolates than amoxicillin (4), are used more disturbed by serotype redistribution, for instance, due to vac- frequently in West Switzerland (Fig. 3). Also, day care atten- cine selection pressure. Therefore, colonizing isolates should dance has been shown to be significantly higher in West Swit- only be used with caution to predict serotype distribution and zerland (20.7 versus 11.9%), although it was not an indepen- resistance among invasive isolates.
dent risk factor for the carriage of PNSP (25). The spread of Age-specific serotype/serogroup distribution of invasive S. penicillin resistance in S. pneumoniae isolates is probably due pneumoniae isolates in this study corresponded well with find- to the geographical spread of a small number of resistant ings in other European countries. The pediatric serotypes 6B, clones rather than a frequent de novo development of resis- 9V, 14, 19F, and 23F predominated among the youngest age tance in individual isolates (22). Therefore, antibiotic selection group, and serotypes 1, 3, 4, 7, 7F, 8, and 22 were relatively pressure as well as easier dissemination in day care centers more prevalent after infancy (15). Serotype 3 accounted for a were probably responsible for the selection of resistant clones larger percentage of invasive disease among young children in in West Switzerland, leading to higher proportions of SSR and Switzerland (13%) than in other European countries (maxi- resistant serotypes in this geographic region. However, there is mum of 5 to 6%) (15). Serotype 3 has rarely been associated some evidence that pneumococcal strains with recently ac- with antibiotic resistance. The high prevalence of serotype 3 quired penicillin resistance may have also been selected (18).
may therefore reflect the relatively low antibiotic selection In conclusion, the epidemiology of invasive and colonizing S. pressure in Switzerland, as discussed below.
pneumoniae isolates is influenced by the serotype-specific poten- The proportion of pediatric serotypes was higher among tial for invasiveness and colonization. Surveillance programs elderly persons than among middle-aged adults. Others have should therefore include both colonizing and invasive S. pneu- also observed this association. However, in this study, the pro- moniae isolates. In addition, antibiotic selection pressure deter- portion of pediatric serotypes among the elderly (34%) was mines the serotype distribution in different age groups and in KRONENBERG ET AL.
different geographic regions. Therefore, it has a significant influ- 17. Hausdorff, W. P. 2002. Invasive pneumococcal disease in children: geo-
ence on the expected direct and indirect effects of PCV-7.
graphic and temporal variations in incidence and serotype distribution. Eur.
J. Pediatr. 161(Suppl. 2):S135–S139.
18. Hauser, C., S. Aebi, and K. Muhlemann. 2004. An internationally spread
clone of Streptococcus pneumoniae evolves from low-level to higher-levelpenicillin resistance by uptake of penicillin-binding protein gene fragments This study was financially supported by the Federal Office of Public from nonencapsulated pneumococci. Antimicrob. Agents Chemother. 48:
Health and Wyeth. We also acknowledge the support from the Swiss 19. Hedlund, J., S. B. Svenson, M. Kalin, J. Henrichsen, B. Olsson-Liljequist, G.
No author has a commercial or other association that might pose a Mollerberg, and G. Kallenius. 1995. Incidence, capsular types, and antibiotic
susceptibility of invasive Streptococcus pneumoniae in Sweden. Clin. Infect.
conflict of interest.
20. Ho, P. L., K. F. Lam, F. K. H. Chow, Y. L. Lau, S. S. Y. Wong, S. L. E. Cheng,
and S. S. Chiu. 2004. Serotype distribution and antimicrobial resistance
1. Brueggemann, A. B., D. T. Griffiths, E. Meats, T. Peto, D. W. Crook, and
patterns of nasopharyngeal and invasive Streptococcus pneumoniae isolates in B. G. Spratt. 2003. Clonal relationships between invasive and carriage Strep-
Hong Kong children. Vaccine 22:3334–3339.
tococcus pneumoniae and serotype- and clone-specific differences in invasive 21. Kellner, J. D., A. McGeer, M. S. Cetron, D. E. Low, J. C. Butler, A. Matlow,
disease potential. J. Infect. Dis. 187:1424–1432.
J. Talbot, and E. L. Ford-Jones. 1998. The use of Streptococcus pneumoniae
2. Brueggemann, A. B., T. E. A. Peto, D. W. Crook, J. C. Butler, K. G. Kristin-
nasopharyngeal isolates from healthy children to predict features of invasive sson, and B. G. Spratt. 2004. Temporal and geographic stability of the
disease. Pediatr. Infect. Dis. J. 17:279–286.
serogroup-specific invasive disease potential of Streptococcus pneumoniae in 22. Klugman, K. P. 2002. The successful clone: the vector of dissemination of
children. J. Infect. Dis. 190:1203–1211.
resistance in Streptococcus pneumoniae. J. Antimicrob. Chemother. 50(Suppl.
3. Buie, K. A., K. P. Klugman, A. von Gottberg, O. Perovic, A. Karstaedt, H. H.
Crewe-Brown, S. A. Madhi, and C. Feldman. 2004. Gender as a risk factor
23. Kyaw, M. H., P. Christie, S. C. Clarke, J. D. Mooney, S. Ahmed, I. G. Jones,
for both antibiotic resistance and infection with pediatric serogroups/sero- and H. Campbell. 2003. Invasive pneumococcal disease in Scotland, 1999-
types, in HIV-infected and -uninfected adults with pneumococcal bacter- 2001: use of record linkage to explore associations between patients and emia. J. Infect. Dis. 189:1996–2000.
disease in relation to future vaccination policy. Clin. Infect. Dis. 37:1283–
4. Canet, J. J., and J. Garau. 2002. Importance of dose and duration of beta-
lactam therapy in nasopharyngeal colonization with resistant pneumococci.
24. Mastro, T. D., N. K. Nomani, Z. Ishaq, A. Ghafoor, N. F. Shaukat, E. Esko,
J. Antimicrob. Chemother. 50(Suppl. S2):39–43.
M. Leinonen, J. Henrichsen, R. F. Breiman, B. Schwartz, et al. 1993. Use of
5. Cars, O., S. Molstad, and A. Melander. 2001. Variation in antibiotic use in
nasopharyngeal isolates of Streptococcus pneumoniae and Haemophilus in- the European Union. Lancet 357:1851–1853.
fluenzae from children in Pakistan for surveillance for antimicrobial resis- 6. Centers for Disease Control and Prevention. 1996. Defining the public
tance. Pediatr. Infect. Dis. J. 12:824–830.
health impact of drug-resistant Streptococcus pneumoniae: report of a work- ¨hlemann, K., H. C. Matter, M. G. Ta
¨uber, and T. Bodmer. 2003. Nation-
ing group. Morb. Mortal. Wkly. Rep. Recomm. Rep. 45(RR-1 Suppl.):1–20.
wide surveillance of nasopharyngeal Streptococcus pneumoniae isolates from 7. Clinical and Laboratory Standards Institute. 2005. Performance standards
children with respiratory infection, Switzerland, 1998-1999. J. Infect. Dis.
for antimicrobial susceptibility testing, fifteenth informational supplement.
Document M100-S14. CLSI, Wayne, Pa.
26. Robinson, D. A., K. M. Edwards, K. B. Waites, D. E. Briles, M. J. Crain, and
8. Colman, G., E. M. Cooke, B. D. Cookson, P. G. Cooper, A. Efstratiou, and
S. K. Hollingshead. 2001. Clones of Streptococcus pneumoniae isolated from
R. C. George. 1998. Pneumococci causing invasive disease in Britain 1982–
nasopharyngeal carriage and invasive disease in young children in central 1990. J. Med. Microbiol. 47:17–27.
Tennessee. J. Infect. Dis. 183:1501–1507. (Erratum, 184:1228.)
9. Ess, S. M., U. B. Schaad, A. Gervaix, S. Pino
¨sch, and T. D. Szucs. 2003.
27. Saha, S. K., A. H. Baqui, G. L. Darmstadt, M. Ruhulamin, M. Hanif, S. El
Cost-effectiveness of a pneumococcal conjugate immunisation program for Arifeen, M. Santosham, K. Oishi, T. Nagatake, and R. E. Black. 2003.
infants in Switzerland. Vaccine 21:3273–3281.
Comparison of antibiotic resistance and serotype composition of carriage 10. Feikin, D. R., K. P. Klugman, R. R. Facklam, E. R. Zell, A. Schuchat, C. G.
and invasive pneumococci among Bangladeshi children: implications for Whitney, et al. 2005. Increased prevalence of pediatric pneumococcal sero-
treatment policy and vaccine formulation. J. Clin. Microbiol. 41:5582–5587.
types in elderly adults. Clin. Infect. Dis. 41:481–487.
28. Sandgren, A., K. Sjo
¨m, B. Olsson-Liljequist, B. Christensson, A. Sam-
11. Filippini, M., G. Masiero, and K. Moschetti. Socioeconomic determinants of
uelsson, G. Kronvall, and B. H. Normark. 2004. Effect of clonal and sero-
regional differences in outpatient antibiotic consumption: evidence from type-specific properties on the invasive capacity of Streptococcus pneu- Switzerland. Health Policy, in press.
moniae. J. Infect. Dis. 189:785–796.
12. Goossens, H., M. Ferech, R. Vander Stichele, M. Elseviers, et al. 2005.
29. Scott, J. A., A. J. Hall, R. Dagan, J. M. Dixon, S. J. Eykyn, A. Fenoll, M.
Outpatient antibiotic use in Europe and association with resistance: a cross- Hortal, L. P. Jette, J. H. Jorgensen, F. Lamothe, C. Latorre, J. T. Macfar-
national database study. Lancet 365:579–587.
lane, D. M. Shlaes, L. E. Smart, and A. Taunay. 1996. Serogroup-specific
13. Hammerschmidt, S., S. Wolff, A. Hocke, S. Rosseau, E. Muller, and M.
epidemiology of Streptococcus pneumoniae: associations with age, sex, and Rohde. 2005. Illustration of pneumococcal polysaccharide capsule during
geography in 7,000 episodes of invasive disease. Clin. Infect. Dis. 22:973–981.
adherence and invasion of epithelial cells. Infect. Immun. 73:4653–4667.
30. Syrjanen, R. K., T. M. Kilpi, T. H. Kaijalainen, E. E. Herva, and A. K.
14. Hanage, W. P., T. H. Kaijalainen, R. K. Syrja
¨nen, K. Auranen, M. Leinonen,
Takala. 2001. Nasopharyngeal carriage of Streptococcus pneumoniae in Finn-
¨, and B. G. Spratt. 2005. Invasiveness of serotypes and clones
ish children younger than 2 years old. J. Infect. Dis. 184:451–459.
of Streptococcus pneumoniae among children in Finland. Infect. Immun.
31. Weiser, J. N., and M. Kapoor. 1999. Effect of intrastrain variation in the
amount of capsular polysaccharide on genetic transformation of Streptococ- 15. Hausdorff, W. P., J. Bryant, P. R. Paradiso, and G. R. Siber. 2000. Which
cus pneumoniae: implications for virulence studies of encapsulated strains.
pneumococcal serogroups cause the most invasive disease: implications for Infect. Immun. 67:3690–3692.
conjugate vaccine formulation and use, part I. Clin. Infect. Dis. 30:100–121.
32. Whitney, C. G., M. M. Farley, and J. Hadler. 2003. Decline in invasive
16. Hausdorff, W. P., D. R. Feikin, and K. P. Klugman. 2005. Epidemiological
pneumococcal disease after the introduction of protein-polysaccharide con- differences among pneumococcal serotypes. Lancet Infect. Dis. 5:83–93.
jugate vaccine. N. Engl. J. Med. 348:1737–1746.


The Impact of a Food For Education Program on Schooling in Cambodia Maria Perrotta† This version: May 15, 2012. First version: May 2009. This study is an evaluation of the impact of a Food for Education program implemented in primary schools (grade 1 to 6) in six Cambodian provinces between 1999 and 2003. We find that school enrollment increased to varying degree in relation to different designs of the intervention. We also investigate

Eneonatal review newsletter, volume 10, issue 7

eNeonatal Review VOLUME 10, ISSUE 7 TREATMENT STRATEGIES FOR GERD IN NEONATES In this Issue. Length of Activity Gastroesophageal reflux (GER), the passage of gastric contents into the esophagus, is 1.0 hour Physicians common in neonates and infants. Regurgitation with clinical y significant sequelae 1.0 contact hour Nurses