778 ARTICLE · 2017. 3. 27. · test using EpiCalc 2000 software version 1.02 (Joe Gilman and MarkMyatt1998,BrixtonBooks)andOpenEpiversion2.3.1(Dean et al. 2011). Differences of p

ARTICLE

Serotype distribution of invasive Streptococcus pneumoniae inCanada after the introduction of the 13-valent pneumococcalconjugate vaccine, 2010–2012Walter H.B. Demczuk, Irene Martin, Averil Griffith, Brigitte Lefebvre, Allison McGeer,Marguerite Lovgren, Gregory J. Tyrrell, Shalini Desai, Lindsey Sherrard, Heather Adam,Matthew Gilmour, George G. Zhanel, the Toronto Bacterial Diseases Network, and the Canadian PublicHealth Laboratory Network

Abstract: The introduction of the 7-valent pneumococcal vaccine (PCV7) in Canada was very effective in reducing invasive pneumo-coccal disease (IPD) in children; however, increases of non-PCV7 serotypes have subsequently offset some of these reductions. A13-valent pneumococcal vaccine (PCV13) targeting additional serotypes was implemented between 2010 and 2011, and in 2012 changesin the incidence of disease and the distribution of IPD serotypes began to emerge. The incidence of IPD in children

sérotypes d’IPI et la diminution de l’incidence de la maladie tendent à démontrer que les programmes de vaccination en vigueurau Canada réduisent efficacement le fardeau d’IPI chez les enfants. Tout en admettant le caractère limité des données sur l’efficacitéréelle du vaccin PCV13, la présente étude représente à nos yeux l’une des premières descriptions de l’impact potentiel du vaccin PCV13sur la population canadienne. Il sera important d’exercer une surveillance continue afin de repérer les sérotypes de remplacement, dedéterminer l’ampleur du phénomène d’immunité collective dans les populations non pédiatriques, et d’évaluer l’efficacité généraledu PCV13 dans la lutte contre l’IPI au Canada. [Traduit par la Rédaction]

Mots-clés : Streptococcus pneumoniae, infection pneumococcique invasive, sérotype, surveillance, PCV13.

IntroductionStreptococcus pneumoniae is a common microorganism that causes

severe invasive pneumococcal diseases (IPDs), such as bacteraemiaand meningitis. Individuals at highest risk of IPD are young childrenand seniors (Scott et al. 1996; Robinson et al. 2001). A 7-valent pneu-mococcal conjugate vaccine (PCV7) targeting 7 serotypes (4, 6B, 9V,14, 18C, 19F, and 23F) of the 93 serotypes was introduced in allCanadian provinces and territories between 2002 and 2006(National Advisory Committee on Immunization 2002; Bettingeret al. 2010) and was very effective in reducing the incidence ofpediatric IPD caused by PCV7 serotypes. During the implementa-tion period, the incidence of IPD among children

cial pool, group, type, and factor antisera (SSI Diagnostica; StatensSerum Institute, Copenhagen, Denmark) (Austrian 1976; Lovgrenet al. 1998). Isolates for which a quellung reaction was not observedwere tested for the presence of the cpsA gene using polymerasechain reaction (Centers for Disease Control and Prevention 2011),and the species was verified by rpoB (beta subunit of RNA polymer-ase gene) sequence typing (Drancourt et al. 2004; Clinical LaboratoryStandards Institute 2008).

In 2011, the NML began a collaborative project with the Univer-sity of Manitoba – Health Sciences Centre – Canadian Antimicro-bial Resistance Alliance to provide antimicrobial susceptibilitytesting for S. pneumoniae isolates submitted to the NML by 8participating jurisdictions. Antimicrobial susceptibilities were de-termined on 2520 isolates submitted in 2011 and 2012 by brothmicrodilution according to Clinical Laboratory Standards Insti-tute guidelines (Clinical Laboratory Standards Institute 2009,2012) for ceftriaxone, chloramphenicol, clarithromycin, clinda-mycin, levofloxacin, penicillin, trimethoprim–sulfamethoxazole,and vancomycin.

Statistical analyses were performed using �2 or Fisher’s exacttest using EpiCalc 2000 software version 1.02 (Joe Gilman andMark Myatt 1998, Brixton Books) and OpenEpi version 2.3.1 (Deanet al. 2011). Differences of p < 0.05 were considered statisticallysignificant.

Results

Isolate informationOf the 8047 isolates analyzed, 2727 were isolated in 2010, 2700 in

2011, and 2620 in 2012. Serotyped isolates represent 97% (889/920) ofthe number of cases reported between 2010 and 2012 in chil-dren

from 7% (185/2727) to 11% (279/2620, p < 0.001), and overall levels ofserotype 3 have remained relatively unchanged (Table 1).

Serotype 19A was common in all clinical isolation sites, represent-ing 17% (1236/7422) of blood, 12% (34/277) of CSF, and 16% (24/147) ofpleural fluid isolates. Serotype 3 represented only 8% (594/7422) ofthe isolates from blood sources but was the most predominant sero-type isolated from CSF and pleural fluid, accounting for 16% (43/277,p < 0.001) and 18% (27/147, p < 0.001) of isolates from those sources,respectively. Serotype 7F represented a higher proportion ofblood isolates (15%, 1082/7422) than CSF (7%, 18/277, p < 0.001) orpleural fluid (7%, 11/147, p = 0.03) isolates. Levels of serotype 22Fwere similar in all clinical sources, representing 9% (634/7422) ofblood, 7% (20/277) of CSF, and 4% (6/147) of pleural fluid isolates.

Age distribution of serotypesOver the 3-year period, dramatic declines in the PCV13 sero-

types 7F and 19A were observed in children

(oral breakpoints), and trimethoprim–sulfamethoxazole. The S. pneu-moniae isolates were universally susceptible to vancomycin.

A trend towards higher resistance rates was noted among thePCV13 serotypes for ceftriaxone, clindamycin, penicillin (intravenousmeningitis and oral breakpoints), and trimethoprim–sulfamethoxazolecompared with the resistance rates of the non-PCV13 serotypes.Lower resistance rates among the PCV13 serotypes compared withnon-PCV13 serotypes were only observed with clarithromycin.

DiscussionFollowing the introduction of PCV13 to all Canadian provinces

and territories, shifts in the overall distribution of pneumococcalserotypes have emerged. PCV13 serotypes have declined overall inCanada since 2010, from 55% of the isolates to 43% in 2012, withthe greatest reductions seen in children

group, from 70% to 40% by 2012 (Fig. 2). The decrease of originalPCV7 serotypes have contributed to the decline of PCV13 serotypesas a whole; however, a greater reduction was attributed to de-creases of the 6 additional PCV13-specific serotypes, particularlyserotype 19A (Table 1).

The introduction of the PCV7 vaccine resulted in swift and sig-nificant reductions in the PCV7 serotypes and in the overall inci-

dence of IPD (Lovgren et al. 1998; Whitney et al. 2003; Lexau et al.2005; Bjornson et al. 2007; Bruce et al. 2008; Winters et al. 2008;Kellner et al. 2009; Tyrrell et al. 2009; Bettinger et al. 2010;Pilishvili et al. 2010; Wong et al. 2012; Lim et al. 2013). After theinitial post-PCV7 decrease from 2004 to 2006, the childhood inci-dence of IPD in Canada increased once again during 2007 to 2009(Public Health Agency of Canada, unpublished data1) mainly due

50–64 years ≥65 years All agesa

2010 2011 2012 2010 2011 2012 2010 2011 2012

2.0 (14) 5.4 (37) 2.7 (19) 2.0 (19) 1.2 (11) 1.8 (17) 2.5 (69) 3.3 (88) 2.4 (63)0.6 (4) 0.4 (3) 0.3 (2) 1.3 (13) 0.9 (8) 1.0 (9) 0.9 (24) 0.5 (14) 0.6 (16)1.6 (11) 0.7 (5) 0.3 (2) 1.1 (11) 0.9 (8) 0.6 (6) 1.2 (32) 0.7 (20) 0.4 (11)0.9 (6) 0.9 (6) 0.3 (2) 1.4 (14) 0.9 (8) 0.7 (7) 1.1 (29) 0.7 (19) 0.5 (13)1.6 (11) 0.9 (6) 1.0 (7) 1.1 (11) 0.2 (2) 0.6 (6) 1.2 (33) 0.5 (13) 0.7 (19)1.3 (9) 0.7 (5) 0.7 (5) 1.6 (15) 1.9 (17) 1.2 (11) 1.8 (48) 1.3 (36) 1.1 (29)0.6 (4) 0.1 (1) 0.3 (2) 1.1 (11) 0.7 (6) 0.9 (8) 0.9 (24) 0.4 (11) 0.4 (11)8.6 (59) 9.1 (63) 5.6 (39) 9.7 (94) 6.6 (60) 6.8 (64) 9.5 (259) 7.4 (201) 6.2 (162)

0.3 (2) 0.4 (3) 0.1 (1) 0.3 (3) 0.1 (1) 0.2 (2) 0.7 (20) 0.5 (13) 0.4 (10)0.4 (3) 0.9 (6) 0.9 (6) 0.1 (1) — 0.2 (2) 0.5 (13) 0.5 (13) 0.5 (12)12.4 (85) 14.5 (100) 12.5 (87) 9.8 (95) 10.6 (97) 7.7 (72) 14.3 (389) 15.1 (407) 12.3 (323)10.5 (72) 8.3 (57) 8.5 (59) 8.8 (85) 10.7 (98) 9.7 (91) 8.3 (226) 8.6 (232) 8.4 (221)2.8 (19) 1.5 (10) 0.6 (4) 3.8 (37) 1.5 (14) 1.8 (17) 2.6 (72) 1.3 (36) 1.0 (27)17.2 (118) 15.7 (108) 12.8 (89) 17.8 (172) 13.8 (126) 12.9 (121) 19.1 (521) 16.1 (436) 13.9 (364)43.5 (299) 41.2 (284) 35.3 (246) 40.6 (393) 36.8 (336) 32.6 (305) 45.5 (1241) 42.1 (1137) 36.5 (957)52.0 (358) 50.4 (347) 40.9 (285) 50.4 (487) 43.3 (396) 39.4 (369) 55.0 (1500) 49.6 (1338) 42.7 (1119)

— — — — — — — — —5.2 (36) 3.9 (27) 4.9 (34) 2.4 (23) 2.0 (18) 2.6 (24) 3.3 (90) 3.3 (90) 3.7 (96)2.9 (20) 5.1 (35) 4.5 (31) 3.2 (31) 2.6 (24) 2.0 (19) 2.4 (65) 3.2 (87) 3.3 (87)1.2 (8) 1.2 (8) 1.3 (9) 1.4 (14) 0.8 (7) 1.4 (13) 1.4 (37) 1.4 (39) 1.5 (40)1.7 (12) 3.3 (23) 3.3 (23) 3.0 (29) 2.7 (25) 3.5 (33) 2.6 (71) 2.8 (76) 3.0 (79)4.8 (33) 3.2 (22) 3.3 (23) 1.3 (13) 2 (18) 1.7 (16) 3.4 (93) 3.0 (80) 3.0 (78)1.0 (7) 0.9 (6) 1.0 (7) 1.7 (16) 1.1 (10) 1.3 (12) 1.5 (41) 1.4 (39) 1.5 (39)1.0 (7) 1.0 (7) 1.0 (7) 1.2 (12) 1.0 (9) 1.3 (12) 0.9 (25) 0.7 (20) 1.0 (25)0.6 (4) 1.0 (7) 2.2 (15) 0.8 (8) 0.8 (7) 1.1 (10) 0.7 (18) 1.0 (26) 2.1 (56)8 (55) 6.2 (43) 10.9 (76) 7.8 (75) 9.8 (90) 13.1 (123) 6.8 (185) 7.8 (210) 10.6 (279)2.6 (18) 1.6 (11) 1.6 (11) 2.0 (19) 1.2 (11) 2.7 (25) 1.8 (49) 1.6 (42) 2.3 (60)29.1 (200) 27.4 (189) 33.9 (236) 24.8 (240) 24.0 (219) 30.6 (287) 24.7 (674) 26.3 (709) 32.0 (839)78.1 (537) 75.9 (523) 74.1 (516) 71 (687) 65.6 (600) 68 (637) 76.3 (2082) 74.0 (1998) 73.3 (1921)

1.7 (12) 2.2 (15) 3.2 (22) 5.4 (52) 6.6 (60) 5.2 (49) 3.1 (84) 3.5 (94) 3.5 (93)2.5 (17) 3.8 (26) 2.3 (16) 4.0 (39) 4.2 (38) 5.9 (55) 3.2 (88) 3.2 (86) 3.5 (93)0.9 (6) 0.7 (5) 0.9 (6) 0.7 (7) 1.1 (10) 1.3 (12) 1.0 (28) 1.4 (37) 1.3 (35)1.3 (9) 1.5 (10) 3.2 (22) 1.9 (18) 1.8 (16) 2.9 (27) 1.6 (43) 1.7 (45) 2.4 (63)2.5 (17) 2.6 (18) 2.9 (20) 3.7 (36) 5.0 (46) 5.3 (50) 2.4 (66) 3.3 (89) 3.6 (94)1.9 (13) 2.6 (18) 3.7 (26) 1.6 (15) 2.2 (20) 2.2 (21) 2.0 (55) 2.1 (56) 3.2 (84)0.7 (5) 0.4 (3) 1.1 (8) 0.5 (5) 1.2 (11) 1.0 (9) 0.4 (11) 0.8 (21) 0.9 (24)0.4 (3) 1.7 (12) 0.7 (5) 0.6 (6) 1.4 (13) — 0.6 (15) 1.3 (36) 0.3 (8)1.3 (9) 0.9 (6) 0.9 (6) 0.8 (8) 1.5 (14) 0.9 (8) 0.7 (20) 0.9 (24) 0.8 (20)1.3 (9) 1.2 (8) 1.4 (10) 0.8 (8) 2.6 (24) 1.5 (14) 1.2 (32) 1.4 (39) 1.4 (36)1.0 (7) 1.2 (8) 1.3 (9) 1.9 (18) 1.4 (13) 1.7 (16) 1.2 (34) 1.0 (28) 1.3 (35)0.4 (3) 0.4 (3) 1.0 (7) 0.8 (8) 1.8 (16) 0.7 (7) 0.6 (16) 1.2 (33) 1.0 (27)2.9 (20) 3.0 (21) 2.6 (18) 2.1 (20) 2.0 (18) 1.4 (13) 2.1 (58) 2.4 (65) 1.9 (50)18.9 (130) 22.2 (153) 25.1 (175) 24.8 (240) 32.7 (299) 30.0 (281) 20.2 (550) 24.2 (653) 25.3 (662)

(688) (689) (696) (967) (914) (937) (2727) (2700) (2620)

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to the emergence of non-PCV7 serotypes such as 7F and 19A(Kellner et al. 2009; Tyrrell et al. 2009; Bettinger et al. 2010; Sahniet al. 2012; Lim et al. 2013). Since 2009, IPD has declined once againin children (Public Health Agency of Canada, unpublished data1),

although the rate of the decrease has been more moderate thanduring the comparable post-PCV7 time frame. It is interesting tonote that the decline of the 6 PCV13-specific serotypes in childrenduring the early implementation of PCV13 in Canada between

Fig. 3. Distribution of pneumococcal serotypes in Canada, 2010–2012. Note: The 13-valent pneumococcal conjugate vaccine (PCV13) includesserotypes 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 7F, 3, 6A, and 19A. The 23-valent polysaccharide pneumococcal vaccine (PPV23) includes all PCV13serotypes except 6A, plus serotypes 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, and 33F. “Other” non-vaccine serotypes include 6D, 7A, 7C, 9A, 9L,10B, 10F, 11B, 11F, 12A, 12B, 13, 15F, 17A, 18A, 18B, 18F, 19B, 19C, 21, 22A, 24F, 24B, 25A, 27, 28A, 29, 33B, 35A, 37, 42, 45, and nontypeable. Theasterisk (*) indicates statistically significant difference from 2010 at p < 0.05.

Table 2. Antimicrobial resistance of Streptococcus pneumoniae in Canada 2011–2012 for all serotypes, 13-valent pneu-mococcal conjugate vaccine (PCV13) serotypes and non-PCV13 serotypes.

All serotypes(n = 2520)

PCV13 serotypes(n = 1119)

Non-PCV13 serotypes(n = 1401)

Antimicrobial agent(CLSI interpretive criteria) %S %I %R %S %I %R %S %I %R

Ceftriaxone (non-meningitis) 98.9 0.9 0.2 92.8 4.6 2.6 100 0 0Ceftriaxone (meningitis) 96.1 2.7 1.2 97.4 2.1 0.5 98.7 1.3 0Chloramphenicol 98.3 0 1.7 98.3 0 1.7 98.4 0 1.6Clarithromycin 75.6 1.1 23.3 78.0 1.4 20.6 73.6 0.9 25.4Clindamycin 91.8 0.3 7.9 91.0 0.5 8.4 92.4 0.1 7.4Levofloxacin 99.4 0.1 0.5 99.6 0 0.4 99.3 0.1 0.6Penicillin (iv non-meningitis) 97.7 2.3 0.04 94.8 5.1 0.1 99.9 0.1 0.0Penicillin (iv meningitis) 87.6 0 12.4 86.4 0 13.6 88.6 0.0 11.4Penicillin (oral, Penicillin V) 87.6 8.7 3.7 86.4 7.1 6.5 88.6 9.9 1.4Trimethoprim–sulfamethoxazole 87.8 6.4 5.8 87.8 2.6 9.6 87.9 9.4 2.7Vancomycin 100 0 0 100 0 0 100 0 0

Note: S, susceptible; I, intermediate; R, resistant.

784 Can. J. Microbiol. Vol. 59, 2013



2010 and 2012 (62% to 39%) is greater than that of PCV7 serotypesduring the early implementation period of PCV7 between 2002 and2004 (77% to 64%) (Bettinger et al. 2010), which may be due to thelonger implementation period of PCV7. However, 4 to 6 years afterthe initial introduction of PCV7 there was a very large decrease ofPCV7 serotypes to 18% (Bettinger et al. 2010), which may suggestfurther declines in the proportion of PCV13 serotypes in the comingyears.

During 2009, a year prior to implementation of the PCV13 vac-cine in Canada, non-PCV7 serotypes accounted for 89% of paediat-ric isolates submitted to the National Centre for Streptococcus,Edmonton, Alberta, of which the 6 PCV13-specific serotypes ac-counted for 54% (Tyrrell 2010). During the transition to the PCV13vaccine, the proportion of the 6 PCV13-specific serotypes decreasedfrom 62% to 52% between 2010 and 2011, and further to 39% in 2012.Similarly, recent reports during the early PCV13 implementationperiod in the United States noted that the 6 PCV13-specific serotypesin children declined from about 62% to 53% between 2008–2009 and2010–2011 (Kaplan et al. 2013; Richter et al. 2013).

Despite a World Health Organization recommendation in 2007that PCV7 be used in all routine childhood immunization pro-grams (World Health Organization 2007), in many parts of theworld, PCV7 serotypes and, therefore, PCV13 serotypes continueto predominate because of inadequate vaccination programs inthese regions (Hackel et al. 2013). Elevated levels of PCV13 sero-types have been reported during 2004–2009 in Africa (79%), Asia-Pacific (68%), Middle East (70%), and Latin America (75%) (Hackelet al. 2013). In Europe the proportion of PCV13 serotypes decreasedfrom representing 76% of IPD reported during 2004–2009 to ap-proximately 60% in 2010 (European Centre for Disease Preventionand Control 2013).

In contrast to reports where the incidence of IPD has rapidlydeclined in older age groups after the introduction of PCV7immunization programs due to reduced carriage and transmis-sion from immunized individuals (Lexau et al. 2005; McBean et al.2005; Isaacman et al. 2007; Kellner et al. 2008; Pilishvili et al. 2010),the incidence of IPD in those ≥5 years of age in Canada increasedsteadily from 5.4 per 100 000 population in 2000 to 9.4 in 2007(Public Health Agency of Canada, unpublished data1) and has re-mained relatively unchanged to 2012. Although this appears tosuggest little or no herd immunity in the older populations, it isgenerally thought that the full impact on disease rates may requireup to 6–7 years postimplementation of the vaccine to be observed(Wong et al. 2012; Nurhonen et al. 2013) and that reductions in vac-cine serotypes may have been offset by concurrent increases of non-vaccine serotypes (Lexau et al. 2005; McBean et al. 2005; Kellner et al.2008, 2009; Tyrrell et al. 2009; Pilishvili et al. 2010; Reinert et al. 2010;Weinberger et al. 2011; Wong et al. 2012). Despite the lack of reduc-tions in incidence in those ≥5 years of age from 2010 to 2012, herdimmunity effects may be evident with a reduction in overall PCV13serotypes in the older age groups (Fig. 2). Further reductions mightbe expected in the older age groups over time, as younger individualsinitially immunized move up into older age categories.

The overall incidence of IPD in Canada has remained relativelyunchanged over the 3-year period at about 9.6 cases of per 100 000,similar to European countries during 2010, such as the UnitedKingdom (9.1), Iceland (10.1), and Slovenia (10.9) (European Centrefor Disease Prevention and Control 2013), as well as the UnitedStates during 2011 with 8.0 cases of IPD per 100 000 population ofreporting states (United States Census Bureau 2012; Centers forDisease Control and Prevention 2013). The highest European inci-dence rates in 2010 were seen in Belgium (17.1), Denmark (17.4),Finland (15.6), Sweden (15.6), and Norway (15.4) (European Centrefor Disease Prevention and Control 2013).

In the present study, while the proportion of 19A and 22F wassomewhat evenly distributed among the clinical isolation sites,serotype 7F was more frequently isolated from blood isolateswhereas serotype 3 was more frequently isolated from pleural

fluid and CSF sources, consistent with previous reports (Hausdorffet al. 2000; Ciruela et al. 2013). Higher CSF isolation rates amongpaediatric cases indicate that children continue to be more sus-ceptible to pneumococcal meningitis than adults as previouslyreported (Dagan et al. 1992).

Shifts in the relative proportions of serotype 19A and 7F inCanada since 2010 reflect trends in overall PCV13 serotypes whereoccurrence has declined significantly first in the

types of antimicrobials used, and population density. In thisstudy, a trend towards higher resistance rates was noted amongthe PCV13 serotypes compared with the non-PCV13 serotypes forthe majority of tested antimicrobial agents. PCV13 serotypes 6B,6A, 9V, 14, 19F, 19A, and 23F are commonly associated with highrates of resistance to penicillin and erythromycin (Lexau et al.2005; Dagan 2009; Liñares et al. 2010; Hackel et al. 2013), and as theutilization of PCV13 vaccine increases, decreases in antimicrobialresistance may be observed. A comprehensive analysis of Canadianpneumococcal isolates is currently being planned by the authorsto describe serotype-specific variations of antimicrobial suscepti-bilities and assess regional and demographic relationships.

IPD has been nationally notifiable in Canada since 2000, with allprovincial and territorial jurisdictions voluntarily reporting casesmeeting the national case definition (Public Health Agency ofCanada 2009) to CNDSS. Information such as serotype, antimicro-bial susceptibilities, vaccine coverage rates, as well as other en-hanced epidemiological patient information such as medical riskfactors, outcome, cultural background, and immunization his-tory were not available from CNDSS. Cases not captured by CNDSSmay include those that do not get medical attention or thosewhere clinical measures were applied with no specimen beingtaken. The laboratory-based, passive surveillance of pneumococ-cal serotype distribution is done collaboratively with jurisdic-tional public health authorities and may be limited by variableregional standards, the preliminary nature of some data, the time-liness of testing and reporting, the availability of isolates for test-ing, and privacy concerns. Although the large majority of IPDcases in Canada are thought to be serotyped, true serotype-specificincidence rates could not be established, and therefore, changesin serotype occurrence were reported as percentage differences.Serotype levels may be biased toward overrepresenting morevirulent serotypes for which medical treatment is sought andmicrobiological specimens were taken. Additionally, pneumococ-cal pneumonia is not considered an invasive disease, so this largeclinical burden is poorly represented by the more complicatedcases of pleural effusion. National serotyping coverage of adultIPD was affected by the hospital-based sentinel surveillance datafrom Quebec, which represented only about 34% of cases ≥5 yearsof age in that province and may have overrepresented antimicrobial-resistant serotypes in that province. Comprehensive serotypingsurveillance systems face further challenges with the introduc-tion of molecular detection techniques, such as PCR for pneumo-coccal disease, where bacterial isolates may not be available forserotyping. Despite these limitations, the passive national surveil-lance program and data submitted by 3 additional reference lab-oratories accounted for 97% of all isolates from children

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ArticleIntroductionMaterials and methodsResultsIsolate informationIncidence of diseasePCV13 serotypesOverall serotype distributionAge distribution of serotypesAntimicrobial resistance

DiscussionConclusions

AcknowledgementsReferences

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778 ARTICLE · 2017. 3. 27. · test using EpiCalc 2000 software version 1.02 (Joe Gilman and MarkMyatt1998,BrixtonBooks)andOpenEpiversion2.3.1(Dean et al. 2011). Differences of p