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Serotype coverage of pneumococcal conjugate vaccine and drug susceptibility of Streptococcus pneumoniae isolated from invasive or non-invasive diseases in central Thailand, 2006–2009
Vaccine 28 (2010) 3440–3444
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Serotype coverage of pneumococcal conjugate vaccine and drug susceptibility of Streptococcus pneumoniae isolated from invasive or non-invasive diseases in central Thailand, 2006–2009 Somporn Srifeungfung a , Chanwit Tribuddharat a , Sopita Comerungsee a , Tanittha Chatsuwan b , Vipa Treerauthanaweeraphong c , Pimpha Rungnobhakhun d , Pongpun Nunthapisud b , Kulkanya Chokephaibulkit e,∗ a
Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand c Microbiological Laboratory, Queen Sirikit National Institute of Child Health, Bangkok, Thailand d Microbiological Laboratory, Bhumipol Aduljadej Hospital, Bangkok, Thailand e Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand b
a r t i c l e
i n f o
Article history: Received 21 November 2009 Received in revised form 29 January 2010 Accepted 15 February 2010 Available online 1 March 2010 Keywords: Streptococcus pneumoniae Serotypes Pneumococcal conjugate vaccine Drug susceptibility Thailand
a b s t r a c t The serotype of 172 S. pneumoniae isolates obtained from normally sterile sites from January 2006 to February 2009 in Thai patients was evaluated. The most common serotypes were 6B, 23F, 14, 19F, and 19A in patients <5 year-old, and 6B, 19A, 23F, 4, 9V in patients >65-year old. Seven-valent pneumococcal conjugated vaccine (PCV-7) covered 70.3%, 43.6%, and 43.5% of patients <5, 5–64 and ≥65 years of age, respectively, while PCV-13 covered 81.2%, 59.7%, and 60.9%, respectively. PCV-9, PCV-10, PCV11 had very similar coverage as PCV-7. The antibiotic susceptibility rates of the isolates from sterile sites were 88.7–95.7% for penicillin, 90.6–98.4% for cefotaxime, 92.2–100% for ofloxacin and 100% for ciprofloxacin. PCV-7 covered 83% and 100%, respectively, of penicillin and cefotaxime non-susceptible isolates in patients <5-year old. © 2010 Elsevier Ltd. All rights reserved.
1. Introduction Streptococcus pneumoniae is an important pathogen accounting for significant morbidity and mortality worldwide particularly in young children and the elderly [1]. A recent report estimated 11–18 million episodes of serious pneumococcal diseases occurred in the year 2000, causing about 826,000 deaths in children younger than 5 years of age [2]. At present, 91 immunologically distinct serotypes of S. pneumoniae have been described, each varying in the structure of their polysaccharide capsule [3,4]. Capsule contributes to the overall virulence and protects S. pneumoniae from phagocytosis. In 2000, the 7-valent pneumococcal-diphtheria CRM197 protein conjugate vaccine (PCV-7; Prevnar; Wyeth, USA) was introduced for pediatric use. The vaccine is composed of the seven serotypes that were the
∗ Corresponding author at: Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkok-noi, Bangkok 10700, Thailand. Tel.: +66 2 419 5671; fax: +66 2 418 0545. E-mail address: [email protected] (K. Chokephaibulkit). 0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.02.071
most common causes of invasive diseases in the US and often confer drug-resistance in children: 19F, 14, 6B, 23F, 9V, 18C, and 4. PCV-7 has been shown to be effective against invasive pneumococcal disease (IPD) caused by serotypes contained in the vaccine [5–7]. After the introduction of PCV-7 in young children, the rates of IPD decreased significantly not only in the vaccinated age group but also in elderly persons who did not receive vaccine [8]. The decline in IPD in the elderly was significant compared to the prior period when pneumococcal polysaccharide vaccine (PPV-23) was the only vaccine available and recommended for the elderly [9,10]. Due to serotype specific efficacy, the better serotype coverage should improve the efficacy of the vaccine. In our previous study [11], we studied pneumococcal isolates from children <5 years old with invasive pneumococcal disease in Thailand from 2000 to 2005 and found serotype coverage of 73.9% and 87.8% by PCV-7 and PCV13, respectively. In June 2006, PCV-7 became available in Thailand, but has not been included in the National Expanded Program of Immunization (EPI). The goal of this study was to monitor serotype coverage of PCV and drug susceptibility in children and adults after vaccine availability. The
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14 (21.9) 14 (21.9) 11 (17.1) 4 (6.2) 4 (6.2) 3 (4.7) 1 (1.6)
21.9 43.8 60.9 67.1 73.3 78.0 79.6
19F 6B 23F 6A 14 18C 3
9 (21.4) 7 (16.7) 7 (16.7) 4 (9.5) 2 (4.7) 1 (2.4) 1 (2.4)
21.4 38.1 54.8 64.3 69.0 71.4 73.8
19F 6B 23F 19A 18C 3 7F
9 (14.5) 7 (11.3) 7 (11.3) 4 (6.5) 3 (4.9) 2 (3.2) 2 (3.2)
14.5 25.8 37.1 43.6 48.5 51.7 54.9
6B 23F 19A 4 9V 19F 3
8 (17.5) 4 (8.7) 4 (8.7) 3 (6.5) 3 (6.5) 2 (4.3) 2 (4.3)
17.5 26.2 34.9 41.4 47.9 52.2 56.5
information from this study may guide vaccine development and direction of health policy.
6B 23F 14 19F 19A 6A 4
No. of isolates (%) Serotype No. of isolates (%) Serotype No. of isolates (%)
Cummulative frequency (%)
No. of isolates (%) Serotype Serotype
Cummulative frequency (%)
Age 5–64 years (sterile sites) N = 62 Age < 5 years (non-sterile sites) N = 42 Age < 5 years (sterile sites) N = 64
Table 1 Seven most frequent conjugate vaccine containing serotypes in descending order in different age categories, Thailand, 2006–2009.
Cummulative frequency (%)
Age ≥ 65 years (sterile sites) N = 46
Cummulative frequency (%)
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2. Methods A total of 174 S. pneumoniae isolates from normally sterile sites were obtained from patients admitted to the hospitals under a collaborative network including 4 tertiary care public hospitals, Siriraj Hospital, Queen Sirikit National Institute of Child Health, King Chulalongkorn Memorial Hospital, Bhumipol Aduljadej Hospital, and 10 other smaller (6 private and 4 public) hospitals, from January 2006 to February 2009. These were all the isolates available from the clinical specimens during the period mentioned at the sites. The catchment area in this study included 3 provinces located in central Thailand (Bangkok, Nakorn Pratom and Nonthaburi). Two isolates died during subculture, therefore 172 isolates were delivered to the microbiological laboratory, Department of Microbiology, Siriraj Hospital for serotyping and drug susceptibility test. Another 42 isolates from non-sterile sites in children younger than 5 years were randomly collected from Siriraj Hospital were included in the study. The isolates were confirmed to be S. pneumoniae by optochin test, bile solubility test and kept at −70 ◦ C in 5% trypticase soy broth plus 20% (v/v) glycerol until use [12]. Multiple isolates from different sites in the same patient were counted only once. Isolates were classified into 3 age groups: group 1: children <5 years with isolates from both sterile sites (total 64: 59 blood, 4 cerebrospinal fluid, 1 pleural fluid) and non-sterile sites (total 42: 32 respiratory specimen, 6 ear swab, 2 eye swab, 2 gastric wash), group 2: patients 5–64 years with isolates from sterile sites only (total 62: 53 blood, 3 cerebrospinal fluid, 6 pleural fluid), and group 3: patients >65 years with isolates from sterile sites only (total 46: 44 blood, 2 pleural fluid). In this study, we performed serotyping and analysed serotype coverage of PCV-7, PCV-9, PCV-10, PCV-11 and PCV-13. PCV-9 is PCV-7 plus 1 and 5. PCV-10 is PCV-9 plus 7F, PCV-11 is PCV-10 plus 3, PCV-13 is PCV-11 plus 6 A and 19A. To determine capsule serotypes of isolates, we performed the Quellung test [11], using various specific group and factor antisera according to the manufacturer’s guideline from the State Serum Institute, Denmark. Typing was done with an addition of a loopful (a few microliters) of methylene blue 0.3% (w/v) in a bacterial suspension on a glass slide, using a microscope (OYMPUS BX 50 Model U-MD08, Oympus Corporation, Tokyo, Japan) with an oil immersion lens (magnification, 10 × 100). The isolates that were not one of the serotypes included in PCV-7, PCV-9, PCV-10, PCV-11 and PCV13 vaccines were not further typed and were labeled as nonvaccine types. Bacterial susceptibility of the isolates to penicillin, cefotaxime, ofloxacin and ciprofloxacin were evaluated by standard microbroth dilution using cation-adjusted Mueller-Hinton broth supplemented with 3% lysed horse blood [13] and E-test method (AB Biodisk, Sweden) according to the manufacturer’s guideline. S. pneumoniae ATCC 49619 was used as the control. The penicillin minimal inhibitory concentrations (MIC) were interpreted as susceptible, intermediate or resistant category according to Clinical Laboratory Standards Institute (CLSI) recommendations [13]. This new criteria take into account whether penicillin is given orally or parenterally and whether a patient has meningitis. Under the former criteria, the isolates from all clinical syndrome and penicillin routes, were interpreted as susceptible, intermediate, and resistant if MIC were ≥0.06, 0.12–1, and ≥2 g/ml, respectively. Under the new criteria, the isolates are classified into 3 categories, i.e., meningitis with parenteral penicillin treatment (susceptible and resistant if MIC are ≤0.06 and ≥0.12 g/ml, respectively); nonmeningitis with parenteral penicillin treatment (susceptible, intermediate and resistant if MIC are ≤2, 4 and ≥8 g/ml, respectively); and
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Table 2 Serotype coverage by 7-, 9-, 10-, 11- and 13-valent pneumococcal conjugate vaccine (PCV) in different age groups, Thailand, 2006–2009. Serotype coverage
<5 years old
5–64 years old
≥65 years old
Sterile sites
Non-sterile sites
Sterile sites
Sterile sites
No. of isolates (%)
No. of isolates (%)
No. of isolates (%)
No. of isolates (%)
4 6B 9V 14 18C 19F 23F
1(1.6) 14(21.9) 1(1.6) 11(17.1) – 4(6.2) 14(21.9)
– 7(16.7) – 2(4.7) 1(2.4) 9(21.4) 7(16.7)
– 7(11.3) 1(1.6) – 3(4.9) 9(14.5) 7(11.3)
3(6.5) 8(17.5) 3(6.5) – – 2(4.3) 4(8.7)
7-PCV coverage 95% CI of percentage
45(70.3) (58.2, 80.1)
26(61.9) (46.8, 75.0)
27(43.6) (31.9, 55.9)
20(43.5) (30.2, 57.8)
1 5
– –
– –
1(1.6) –
1(2.2) –
9-PCV coverage 95% CI of percentage
45(70.3) (58.2, 80.1)
26(61.9) (46.8, 75.0)
28(45.2) (33.4, 57.5)
21(45.7) (32.2, 59.8)
7F
–
–
2(3.2)
1(2.2)
10-PCV coverage 95% CI of percentage
45(70.3) (58.2, 80.1)
26(61.9) (46.8, 75.0)
30(48.4) (36.4, 60.6)
22(47.9) (34.1, 61.9)
3 11-PCV coverage 95% CI of percentage
– 45(70.3) (58.2, 80.1)
1(2.4) 27(64.3) (49.2, 77.0)
2(3.2) 32(51.6) (39.4, 63.6)
2(4.3) 24(52.2) (38.1, 65.9)
6A 19A
3(4.7) 4(6.2)
4(9.5) 1(2.4)
1(1.6) 4(6.5)
– 4(8.7)
13-PCV coverage 95% CI of percentage
52(81.2) (70.0, 88.9)
32(76.2) (61.5, 86.5)
37(59.7) (47.3, 70.9)
28(60.9) (46.5, 73.6)
Nonvaccine serotype All isolates
12(18.8) 64(100)
10(23.8) 42(100)
25(40.3) 62(100)
18(39.1) 46(100)
non-meningitis with oral penicillin treatment (susceptible, intermediate, and resistant if MIC were ≤0.06, 0.12–1, and ≥2 g/ml), respectively. The criterion for resistance to ciprofloxacin was MIC ≥4 g/ml [14]; S. aureus ATCC 25923 was used as the control. The descriptive analysis was used in this study. The rates of vaccine coverage were presented with 95% confidential interval. 3. Results Of the 214 isolates, 172 from sterile sites and 42 from non-sterile sites, the seven most frequent vaccine containing serotypes from isolates from sterile sites in patients <5 years old were 6B, 23F, 14, 19F, 19A, 6A, and 4 or 9V, accounting for 81.2% of all isolates. For the patients ≥65 years old, the seven most common serotypes were 6B, 23F, 19A, 4, 9V, 19F and 3, accounting for 56.5% of all isolates (Table 1). Serotype 6B and 23F were the most frequently identified serotype from sterile sites in patients <5 and ≥65 years old. The serotype coverage of vaccines is shown in Table 2. PCV7 covered 70.3%, 43.6%, and 43.5% of S. pneumoniae isolates from sterile sites in patients <5 years, 5–64 years, and ≥65 years old, respectively. PCV-13 provided coverage to 81.2%, 59.7%, and 60.9% of isolates from patients in these age groups, respectively. Other PCVs (PCV-9, PCV-10, PCV-11) had similar coverage as PCV-7 in patients <5 years old, but slightly increased coverage in patients 5–64 years and ≥65 years (range 43.5–52.2%). In children <5 years of age, PCV-7 and PCV-13 covered 61.9% and 76.2% of isolates from non-sterile sites, respectively. For the analysis in this study, we used meningitis criteria for S. pneumoniae isolates from CSF only, and non-meningitis criteria for those from other sites (Table 3). With this analysis strategy, we found the penicillin susceptibility rates in isolates from sterile sites were 93.8%, 88.7% and 95.7% in patients <5, 5–64 and ≥65 years old, respectively.
The corresponding percentages for cefotaxime susceptibility were 90.6%, 98.4% and 93.5%, respectively. In contrast, penicillinand cefotaxime-susceptibility rates in isolates from non-sterile sites in patients <5 years old using criteria for non-meningitis and with oral penicillin treatment were 26.2% and 78.6%, respectively. The MICs for all antibiotics tested in isolates from non-sterile sites were higher than those from sterile sites. Susceptibility to ofloxacin ranged 92.2–100%, and all isolates were susceptible to ciprofloxacin. PCV-7 covered 83% and 100% of penicillin and cefotaxime non-susceptible isolates, respectively, from sterile sites in patients <5 years old. We demonstrated comparison of penicillin susceptibility of isolates from sterile sites in <5 years old using the former and the newer criteria in Fig. 1. If we used the former criteria, only 28.1% would be penicillin-susceptible S. pneumoniae (PSSP). 4. Discussion Our study describes the serotype distribution and antimicrobial susceptibilities of invasive pneumococcal isolates collected in Thailand from 2006 to 2009. Data on a small set of non-invasive isolates from children under five were also presented. Although this is a relatively small number of isolates from a limited geographic range, these results represent an important contribution, and presented several years of monitoring continuum from our previous report, to the very limited data on pneumococcal serotypes in this region. PCV-7 has been shown in many studies to be highly immunogenic and effective against IPD [5,15–17], with the vaccine efficacy of 97.4% against vaccine serotypes in the US [5]. In the large trial in South Africa and Gambia, the efficacy of PCV-9 was 83% and 77% against IPD caused by vaccine serotypes [18,19]. Twice as many IPD cases were indirectly prevented due to herd immunity after the PCV-7 implementation in the US [8]. Due to serotype specific effi-
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Table 3 Percentage of S. pneumoniae isolates sensitive to antibiotic drugs using the new Clinical Laboratory Standards Institute criteria, Thailand, 2006–2009. Drugs
<5 years old
Penicillin Cefotaxime Ofloxacin Ciprofloxacin
≥65 years old
5–64 years old
a
Sterile sites (n = 64)
Non-sterile sites (n = 42)
Sterile sites (n = 62)
Sterile sitesa (n = 46)
% susceptable
% susceptable
% susceptable
% susceptable
93.8 90.6 92.2 100
b
MICs (g/ml) MIC50
MIC90
0.25 0.25 2 0.5
2 1 2 1
26.2 78.6 100 100
a
MICs (g/ml) MIC50
MIC90
2 0.5 2 1
4 2 2 2
88.7 98.4 96.8 100
MICs (g/ml) MIC50
MIC90
0.5 0.06 1 1
2 0.5 2 2
95.7 93.5 93.5 100
MICs (g/ml) MIC50
MIC90
0.125 0.125 2 0.5
2 2 2 2
MIC50 and MIC90 are the minimal inhibitory concentration required to inhibit the growth of 50% and 90% of pneumococci, respectively. a The MIC breakpoints used for isolates from sterile sites based on criteria for meningitis if isolates were from CSF, and criteria for non-meningitis disease with intravenous penicillin for isolates from other sterile sites. b The MIC breakpoints used for isolates from non-sterile site based on the criteria for non-meningitis disease with oral penicillin.
cacy of the vaccine, serotype coverage of IPD implies and predicts the efficacy of the vaccine. In this region, the serotype coverage of 70.3% by PCV-7 in IPD in children under five years of age in our study was less than the 78% coverage found in Singapore [15], but higher than in a study in China in 2008 which found 63.6%, 64.8% and 79.6% coverage by PCV-7, PCV-10 and PCV-13, respectively [20]. The serotype coverage of IPD isolates by PCV-7 in children ≤14 years old in Taiwan was 85%, somewhat higher than in our study [21]. WHO reported the overall serotype coverage of PCV-7 ranged from 60 to 85% worldwide [22]. There has been a concern about the increased proportion of nonvaccine serotypes reported in the US and Spain after introduction of PCV-7 vaccination program [8,23,24]. The widely use of PCV-7 may contributed to the emergence of nonvaccine serotypes, especially serotype 19A [8,23,24]. However, a study in Korea reported an increase in serotype 19A even before the introduction of PCV-7 [25]. It is probable that both selective vaccine pressure and clonal spread were contributing factors to the circulating serotypes in the community. In Thailand, we reported the serotype coverage of PCV-7, PCV-9, PCV-11, and PCV-13 of 73.9%, 77.4%, 77.4%, and 87.8%, respectively, in children younger than 5 years of age during 2001–2005 [11]. The serotype coverage found in this study was somewhat lower than that report, but was still within the 95% confidential interval. Although PCV-7 has been available in Thailand since June 2006, the vaccine has been used mainly in private set-
Fig. 1. Penicillin susceptibility of S. pneumoniae isolated from sterile sites in children <5 years old using former and new CLSI criteria, Thailand, 2006–2009. Former criteria: susceptible, intermediate, and resistant MIC for penicillin were ≤0.06, 0.12–1, and ≥2 g/ml, respectively, for all pneumococcal isolates, regardless of clinical syndrome or route of penicillin administration. New criteria: susceptible and resistant MIC are ≤0.06 and ≥0.12 g/ml, respectively, for meningitis with intravenous penicillin; and susceptible, intermediate and resistant MIC are ≤2, 4, and ≥8 g/ml, respectively, for nonmeningitis with intravenous penicillin. The non-meningitis criteria was used for S. pneumoniae isolated from blood, and meningitis criteria was used for CSF.
tings with an estimated 55,000 doses sold each year, representing less than 5% of children <5 years of age. This low vaccine uptake did not seem to affect the serotype distribution in this relatively small study. The top seven serotypes of invasive isolates found in our study were different in rank of order and frequency (%) in each age groups, as well as whether the sites were sterile or non-sterile. Although the top seven serotypes of isolates from sterile sites in children younger than 5 years of age were not completely match with other studies reported earlier in Thailand [11,26–28], they were quite consistent. The common serotypes found in those and our studies were 6B, 14, 19A, 19F, 23F. The PCV that included all these serotypes, i.e. PCV-13, would be the most appropriate for large scale use in Thailand. The presence of cefotaxime-non-susceptible isolates from sterile sites, although few, are of concern because cefotaxime has been the main antibiotic used for treatment of pneumococcal meningitis. Currently, cefotaxime combine with vancomycin have been recommended as empirical treatment in meningitis until the susceptibility become available. The first clinical isolate that was highly resistant to ciprofloxacin (MIC > 32 g/ml) and other newer fluoroquinolones was reported in 1999 [29]. However, the reported prevalence of resistance to fluoroquinolones is relatively low (typically <0.5%) [30], and we found similar results in this study. The new criteria for penicillin susceptibility has increased the percentage of penicillin susceptible in non-meningitis isolates from sterile site treated with parenteral penicillin, and was more correlate with the clinical use [13]. Interpretation in the patients with clinical meningitis, of whom the organism was isolated out from blood only, should use the breakpoint for meningitis in such isolates. Due to the lack of clinical information in this study, we used the meningitis criteria only for CSF isolates, and non-menigitis criteria for all blood isolates, and therefore may have resulted in overestimation of penicillin susceptibility in some meningitis cases. However, the impact from this should be minimal as penicillin is not currently recommended for empirical treatment of meningitis. We found low rates of penicillin non-susceptibility of 4–11% in isolates from sterile sites of all age, but very high rate of 73.8% among isolates from non-sterile sites in young children. This latter information is of concern because it increased from 63% in 1997–1998 in our institution [31], to 69% in the year 2004–2005 [32], using the same cut-off levels. The MIC50 and MIC90 increased from 0.5 and 2 g/ml in 1997–1998 to 2 and 4 g/ml, respectively, in 2006–2009. Of note was that the MIC50 and MIC90 of isolates from sterile sites were unchanged over the time. These results needed to be communicated to clinicians for appropriate and judicious antibiotic therapy. The limitations of this study included a potential limited geographic representative; the isolates were mainly from central Thailand, and the relatively small numbers of total isolates. The lack of information on geographic distribution of PCV-7 uptake, partic-
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ularly with overall low uptake rate, made it impossible to evaluate any impact of the vaccine. In conclusion, this study found that the serotype distribution and coverage of all PCVs for S. pneumoniae in Thailand remain unchanged since the vaccine has been available in 2006. The licensing process of PCV-10 and PCV-13 in Thailand are in progress, and this study provides basic information to support the evaluation and impact of other PCVs in the future. Continued surveillance for pneumococcal serotypes and susceptibilities are crucial to provide information on emerging pneumococcal serotypes and the optimal composition of future conjugate vaccines as well as the impact of the vaccine after wide-spread use. Moreover, antimicrobial susceptibility can inform guidelines for selection of appropriate drugs for treatment of pneumococcal infections. Acknowledgements This work was funded by Wyeth-Ayerst (Thailand) Ltd. and in part by the Faculty of Medicine Siriraj Hospital, Mahidol University. We thank the following hospitals for supplying pneumococcal isolates: Bangkok Hospital, Bhummipol Hospital, Bumrungrad International Hospital, Chaophya Hospital, King Chulalongkorn Memorial Hospital, Mongkutwattana General Hospital, Phayathai Hospital, Queen Sirikit National Institute of Child Heath, Nakorn Pratom Hospital, Rajavithi Hospital, Ramkhamhaeng Hospital, Somdejprapinklao Hospital and Taksin Hospital. We thank Dr. Michelle McConnell for her critical inputs and helps to this manuscript. References [1] Obaro SK, Monteil MA, Henderson DC. The pneumococcal problem. BMJ 1996;312(7045):1521–5. [2] O’Brien KL, Wolfson LJ, Watt JP, Henkle E, Deloria-Knoll M, McCall N, et al. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 2009;374(9693):893–902. [3] Henrichsen J. Six newly recognized types of Streptococcus pneumoniae. J Clin Microbiol 1995;33(10):2759–62. [4] Park IH, Pritchard DG, Cartee R, Brandao A, Brandileone MC, Nahm MH. Discovery of a new capsular serotype (6C) within serogroup 6 of Streptococcus pneumoniae. J Clin Microbiol 2007;45(4):1225–33. [5] Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000;19(3):187–95. [6] American Academy of Pediatrics. Committee on Infectious Diseases. Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics 2000;106(2 (Pt 1)):362–6. [7] Ruckinger S, van der Linden M, Reinert RR, von Kries R, Burckhardt F, Siedler A. Reduction in the incidence of invasive pneumococcal disease after general vaccination with 7-valent pneumococcal conjugate vaccine in Germany. Vaccine 2009;27(31):4136–41. [8] Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease—United States, 1998–2003. MMWR Morb Mortal Wkly Rep 2005;54(36):893–7. [9] McBean AM, Park YT, Caldwell D, Yu X. Declining invasive pneumococcal disease in the U.S. elderly. Vaccine 2005;23(48–49):5641–5. [10] Lexau CA, Lynfield R, Danila R, Pilishvili T, Facklam R, Farley MM, et al. Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine. JAMA 2005;294(16):2043–51.
[11] Phongsamart W, Srifeungfung S, Dejsirilert S, Chatsuwan T, Nunthapisud P, Treerauthaweeraphong V, et al. Serotype distribution and antimicrobial susceptibility of S. pneumoniae causing invasive disease in Thai children younger than 5 years old, 2000–2005. Vaccine 2007;25(7):1275–80. [12] Ruoff KL, Whiley RA, Beighton D. Streptococcus. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, editors. Manual of Clinical Microbiology. Washington, D.C., USA: ASM Press; 2003. p. 405–21. [13] Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial and susceptibility testing: 15th Informational Supplement (M100-S18). Wayne, PA: Clinical and Laboratory Standards Institute; 2008. [14] De Vecchi E, Nicola L, Ossola F, Drago L. In vitro selection of resistance in Streptococcus pneumoniae at in vivo fluoroquinolone concentrations. J Antimicrob Chemother 2009;63(4):721–7. [15] Chong CY, Koh-Cheng T, Yee-Hui M, Nancy TW. Invasive pneumococcal disease in Singapore children. Vaccine 2008;26(27–28):3427–31. [16] Shinefield HR, Black S. Efficacy of pneumococcal conjugate vaccines in large scale field trials. Pediatr Infect Dis J 2000;19(4):394–7. [17] Nachman S, Kim S, King J, Abrams EJ, Margolis D, Petru A, et al. Safety and immunogenicity of a heptavalent pneumococcal conjugate vaccine in infants with human immunodeficiency virus type 1 infection. Pediatrics 2003;112(1 (Pt 1)):66–73. [18] Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003;349(14):1341–8. [19] Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS, Okoko JB, et al. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebocontrolled trial. Lancet 2005;365(9465):1139–46. [20] Liu Y, Wang H, Chen M, Sun Z, Zhao R, Zhang L, et al. Serotype distribution and antimicrobial resistance patterns of Streptococcus pneumoniae isolated from children in China younger than 5 years. Diagn Microbiol Infect Dis 2008;61(3):256–63. [21] Lin WJ, Lo WT, Chou CY, Chen YY, Tsai SY, Chu ML, et al. Antimicrobial resistance patterns and serotype distribution of invasive Streptococcus pneumoniae isolates from children in Taiwan from 1999 to 2004. Diagn Microbiol Infect Dis 2006;56(2):189–96. [22] Pneumococcal conjugate vaccine for childhood immunization—WHO position paper. Wkly Epidemiol Rec 2007;82(12):93–104. [23] Steenhoff AP, Shah SS, Ratner AJ, Patil SM, McGowan KL. Emergence of vaccinerelated pneumococcal serotypes as a cause of bacteremia. Clin Infect Dis 2006;42(7):907–14. [24] Munoz-Almagro C, Jordan I, Gene A, Latorre C, Garcia-Garcia JJ, Pallares R. Emergence of invasive pneumococcal disease caused by nonvaccine serotypes in the era of 7-valent conjugate vaccine. Clin Infect Dis 2008;46(2):174–82. [25] Choi EH, Kim SH, Eun BW, Kim SJ, Kim NH, Lee J, et al. Streptococcus pneumoniae serotype 19A in children, South Korea. Emerg Infect Dis 2008;14(2): 275–81. [26] Watanabe H, Asoh N, Hoshino K, Watanabe K, Oishi K, Kositsakulchai W, et al. Antimicrobial susceptibility and serotype distribution of Streptococcus pneumoniae and molecular characterization of multidrug-resistant serotype 19F, 6B, and 23F Pneumococci in northern Thailand. J Clin Microbiol 2003;41(9):4178–83. [27] Srifeungfung S, Chokephaibulkit K, Tribuddharat C. Serotypes and antimicrobial susceptibilities of Streptococcus pneumoniae isolated from hospitalized patients in Thailand. Southeast Asian J Trop Med Public Health 2007;38(3):469–77. [28] Baggett HC, Peruski LF, Olsen SJ, Thamthitiwat S, Rhodes J, Dejsirilert S, et al. Incidence of pneumococcal bacteremia requiring hospitalization in rural Thailand. Clin Infect Dis 2009;48(Suppl. 2):S65–74. [29] Hsueh PR, Luh KT. Antimicrobial resistance in Streptococcus pneumoniae, Taiwan. Emerg Infect Dis 2002;8(12):1487–91. [30] Appelbaum PC. Resistance among Streptococcus pneumoniae: implications for drug selection. Clin Infect Dis 2002;34(12):1613–20. [31] Chokephaibulkit K, Srifuengfung S, Mingbanjerdsuk J, Tosasuk K, Vanprapar N, Chearskul S, et al. Evaluation of susceptibility status of invasive pneumococcal isolates to various antibiotics and risk factors associated with invasive penicillin-nonsusceptible pneumococcal infection: Bangkok 1997–1998. Southeast Asian J Trop Med Public Health 2000;31(3):498– 505. [32] Srifuengfung S, Tribuddharat C, Champreeda P, Daniels J, Chokephaibulkit K, Wongwan N, et al. Antimicrobial susceptibility of Streptococcus pneumoniae isolated from patients with respiratory tract infections in Thailand. Southeast Asian J Trop Med Public Health 2008;39(3):461–6.
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Serotype coverage of pneumococcal conjugate vaccine and drug susceptibility of Streptococcus pneumoniae isolated from invasive or non-invasive diseases in central Thailand, 2006–2009 Somporn Srifeungfung a , Chanwit Tribuddharat a , Sopita Comerungsee a , Tanittha Chatsuwan b , Vipa Treerauthanaweeraphong c , Pimpha Rungnobhakhun d , Pongpun Nunthapisud b , Kulkanya Chokephaibulkit e,∗ a
Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand c Microbiological Laboratory, Queen Sirikit National Institute of Child Health, Bangkok, Thailand d Microbiological Laboratory, Bhumipol Aduljadej Hospital, Bangkok, Thailand e Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand b
a r t i c l e
i n f o
Article history: Received 21 November 2009 Received in revised form 29 January 2010 Accepted 15 February 2010 Available online 1 March 2010 Keywords: Streptococcus pneumoniae Serotypes Pneumococcal conjugate vaccine Drug susceptibility Thailand
a b s t r a c t The serotype of 172 S. pneumoniae isolates obtained from normally sterile sites from January 2006 to February 2009 in Thai patients was evaluated. The most common serotypes were 6B, 23F, 14, 19F, and 19A in patients <5 year-old, and 6B, 19A, 23F, 4, 9V in patients >65-year old. Seven-valent pneumococcal conjugated vaccine (PCV-7) covered 70.3%, 43.6%, and 43.5% of patients <5, 5–64 and ≥65 years of age, respectively, while PCV-13 covered 81.2%, 59.7%, and 60.9%, respectively. PCV-9, PCV-10, PCV11 had very similar coverage as PCV-7. The antibiotic susceptibility rates of the isolates from sterile sites were 88.7–95.7% for penicillin, 90.6–98.4% for cefotaxime, 92.2–100% for ofloxacin and 100% for ciprofloxacin. PCV-7 covered 83% and 100%, respectively, of penicillin and cefotaxime non-susceptible isolates in patients <5-year old. © 2010 Elsevier Ltd. All rights reserved.
1. Introduction Streptococcus pneumoniae is an important pathogen accounting for significant morbidity and mortality worldwide particularly in young children and the elderly [1]. A recent report estimated 11–18 million episodes of serious pneumococcal diseases occurred in the year 2000, causing about 826,000 deaths in children younger than 5 years of age [2]. At present, 91 immunologically distinct serotypes of S. pneumoniae have been described, each varying in the structure of their polysaccharide capsule [3,4]. Capsule contributes to the overall virulence and protects S. pneumoniae from phagocytosis. In 2000, the 7-valent pneumococcal-diphtheria CRM197 protein conjugate vaccine (PCV-7; Prevnar; Wyeth, USA) was introduced for pediatric use. The vaccine is composed of the seven serotypes that were the
∗ Corresponding author at: Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkok-noi, Bangkok 10700, Thailand. Tel.: +66 2 419 5671; fax: +66 2 418 0545. E-mail address: [email protected] (K. Chokephaibulkit). 0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.02.071
most common causes of invasive diseases in the US and often confer drug-resistance in children: 19F, 14, 6B, 23F, 9V, 18C, and 4. PCV-7 has been shown to be effective against invasive pneumococcal disease (IPD) caused by serotypes contained in the vaccine [5–7]. After the introduction of PCV-7 in young children, the rates of IPD decreased significantly not only in the vaccinated age group but also in elderly persons who did not receive vaccine [8]. The decline in IPD in the elderly was significant compared to the prior period when pneumococcal polysaccharide vaccine (PPV-23) was the only vaccine available and recommended for the elderly [9,10]. Due to serotype specific efficacy, the better serotype coverage should improve the efficacy of the vaccine. In our previous study [11], we studied pneumococcal isolates from children <5 years old with invasive pneumococcal disease in Thailand from 2000 to 2005 and found serotype coverage of 73.9% and 87.8% by PCV-7 and PCV13, respectively. In June 2006, PCV-7 became available in Thailand, but has not been included in the National Expanded Program of Immunization (EPI). The goal of this study was to monitor serotype coverage of PCV and drug susceptibility in children and adults after vaccine availability. The
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14 (21.9) 14 (21.9) 11 (17.1) 4 (6.2) 4 (6.2) 3 (4.7) 1 (1.6)
21.9 43.8 60.9 67.1 73.3 78.0 79.6
19F 6B 23F 6A 14 18C 3
9 (21.4) 7 (16.7) 7 (16.7) 4 (9.5) 2 (4.7) 1 (2.4) 1 (2.4)
21.4 38.1 54.8 64.3 69.0 71.4 73.8
19F 6B 23F 19A 18C 3 7F
9 (14.5) 7 (11.3) 7 (11.3) 4 (6.5) 3 (4.9) 2 (3.2) 2 (3.2)
14.5 25.8 37.1 43.6 48.5 51.7 54.9
6B 23F 19A 4 9V 19F 3
8 (17.5) 4 (8.7) 4 (8.7) 3 (6.5) 3 (6.5) 2 (4.3) 2 (4.3)
17.5 26.2 34.9 41.4 47.9 52.2 56.5
information from this study may guide vaccine development and direction of health policy.
6B 23F 14 19F 19A 6A 4
No. of isolates (%) Serotype No. of isolates (%) Serotype No. of isolates (%)
Cummulative frequency (%)
No. of isolates (%) Serotype Serotype
Cummulative frequency (%)
Age 5–64 years (sterile sites) N = 62 Age < 5 years (non-sterile sites) N = 42 Age < 5 years (sterile sites) N = 64
Table 1 Seven most frequent conjugate vaccine containing serotypes in descending order in different age categories, Thailand, 2006–2009.
Cummulative frequency (%)
Age ≥ 65 years (sterile sites) N = 46
Cummulative frequency (%)
S. Srifeungfung et al. / Vaccine 28 (2010) 3440–3444
2. Methods A total of 174 S. pneumoniae isolates from normally sterile sites were obtained from patients admitted to the hospitals under a collaborative network including 4 tertiary care public hospitals, Siriraj Hospital, Queen Sirikit National Institute of Child Health, King Chulalongkorn Memorial Hospital, Bhumipol Aduljadej Hospital, and 10 other smaller (6 private and 4 public) hospitals, from January 2006 to February 2009. These were all the isolates available from the clinical specimens during the period mentioned at the sites. The catchment area in this study included 3 provinces located in central Thailand (Bangkok, Nakorn Pratom and Nonthaburi). Two isolates died during subculture, therefore 172 isolates were delivered to the microbiological laboratory, Department of Microbiology, Siriraj Hospital for serotyping and drug susceptibility test. Another 42 isolates from non-sterile sites in children younger than 5 years were randomly collected from Siriraj Hospital were included in the study. The isolates were confirmed to be S. pneumoniae by optochin test, bile solubility test and kept at −70 ◦ C in 5% trypticase soy broth plus 20% (v/v) glycerol until use [12]. Multiple isolates from different sites in the same patient were counted only once. Isolates were classified into 3 age groups: group 1: children <5 years with isolates from both sterile sites (total 64: 59 blood, 4 cerebrospinal fluid, 1 pleural fluid) and non-sterile sites (total 42: 32 respiratory specimen, 6 ear swab, 2 eye swab, 2 gastric wash), group 2: patients 5–64 years with isolates from sterile sites only (total 62: 53 blood, 3 cerebrospinal fluid, 6 pleural fluid), and group 3: patients >65 years with isolates from sterile sites only (total 46: 44 blood, 2 pleural fluid). In this study, we performed serotyping and analysed serotype coverage of PCV-7, PCV-9, PCV-10, PCV-11 and PCV-13. PCV-9 is PCV-7 plus 1 and 5. PCV-10 is PCV-9 plus 7F, PCV-11 is PCV-10 plus 3, PCV-13 is PCV-11 plus 6 A and 19A. To determine capsule serotypes of isolates, we performed the Quellung test [11], using various specific group and factor antisera according to the manufacturer’s guideline from the State Serum Institute, Denmark. Typing was done with an addition of a loopful (a few microliters) of methylene blue 0.3% (w/v) in a bacterial suspension on a glass slide, using a microscope (OYMPUS BX 50 Model U-MD08, Oympus Corporation, Tokyo, Japan) with an oil immersion lens (magnification, 10 × 100). The isolates that were not one of the serotypes included in PCV-7, PCV-9, PCV-10, PCV-11 and PCV13 vaccines were not further typed and were labeled as nonvaccine types. Bacterial susceptibility of the isolates to penicillin, cefotaxime, ofloxacin and ciprofloxacin were evaluated by standard microbroth dilution using cation-adjusted Mueller-Hinton broth supplemented with 3% lysed horse blood [13] and E-test method (AB Biodisk, Sweden) according to the manufacturer’s guideline. S. pneumoniae ATCC 49619 was used as the control. The penicillin minimal inhibitory concentrations (MIC) were interpreted as susceptible, intermediate or resistant category according to Clinical Laboratory Standards Institute (CLSI) recommendations [13]. This new criteria take into account whether penicillin is given orally or parenterally and whether a patient has meningitis. Under the former criteria, the isolates from all clinical syndrome and penicillin routes, were interpreted as susceptible, intermediate, and resistant if MIC were ≥0.06, 0.12–1, and ≥2 g/ml, respectively. Under the new criteria, the isolates are classified into 3 categories, i.e., meningitis with parenteral penicillin treatment (susceptible and resistant if MIC are ≤0.06 and ≥0.12 g/ml, respectively); nonmeningitis with parenteral penicillin treatment (susceptible, intermediate and resistant if MIC are ≤2, 4 and ≥8 g/ml, respectively); and
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Table 2 Serotype coverage by 7-, 9-, 10-, 11- and 13-valent pneumococcal conjugate vaccine (PCV) in different age groups, Thailand, 2006–2009. Serotype coverage
<5 years old
5–64 years old
≥65 years old
Sterile sites
Non-sterile sites
Sterile sites
Sterile sites
No. of isolates (%)
No. of isolates (%)
No. of isolates (%)
No. of isolates (%)
4 6B 9V 14 18C 19F 23F
1(1.6) 14(21.9) 1(1.6) 11(17.1) – 4(6.2) 14(21.9)
– 7(16.7) – 2(4.7) 1(2.4) 9(21.4) 7(16.7)
– 7(11.3) 1(1.6) – 3(4.9) 9(14.5) 7(11.3)
3(6.5) 8(17.5) 3(6.5) – – 2(4.3) 4(8.7)
7-PCV coverage 95% CI of percentage
45(70.3) (58.2, 80.1)
26(61.9) (46.8, 75.0)
27(43.6) (31.9, 55.9)
20(43.5) (30.2, 57.8)
1 5
– –
– –
1(1.6) –
1(2.2) –
9-PCV coverage 95% CI of percentage
45(70.3) (58.2, 80.1)
26(61.9) (46.8, 75.0)
28(45.2) (33.4, 57.5)
21(45.7) (32.2, 59.8)
7F
–
–
2(3.2)
1(2.2)
10-PCV coverage 95% CI of percentage
45(70.3) (58.2, 80.1)
26(61.9) (46.8, 75.0)
30(48.4) (36.4, 60.6)
22(47.9) (34.1, 61.9)
3 11-PCV coverage 95% CI of percentage
– 45(70.3) (58.2, 80.1)
1(2.4) 27(64.3) (49.2, 77.0)
2(3.2) 32(51.6) (39.4, 63.6)
2(4.3) 24(52.2) (38.1, 65.9)
6A 19A
3(4.7) 4(6.2)
4(9.5) 1(2.4)
1(1.6) 4(6.5)
– 4(8.7)
13-PCV coverage 95% CI of percentage
52(81.2) (70.0, 88.9)
32(76.2) (61.5, 86.5)
37(59.7) (47.3, 70.9)
28(60.9) (46.5, 73.6)
Nonvaccine serotype All isolates
12(18.8) 64(100)
10(23.8) 42(100)
25(40.3) 62(100)
18(39.1) 46(100)
non-meningitis with oral penicillin treatment (susceptible, intermediate, and resistant if MIC were ≤0.06, 0.12–1, and ≥2 g/ml), respectively. The criterion for resistance to ciprofloxacin was MIC ≥4 g/ml [14]; S. aureus ATCC 25923 was used as the control. The descriptive analysis was used in this study. The rates of vaccine coverage were presented with 95% confidential interval. 3. Results Of the 214 isolates, 172 from sterile sites and 42 from non-sterile sites, the seven most frequent vaccine containing serotypes from isolates from sterile sites in patients <5 years old were 6B, 23F, 14, 19F, 19A, 6A, and 4 or 9V, accounting for 81.2% of all isolates. For the patients ≥65 years old, the seven most common serotypes were 6B, 23F, 19A, 4, 9V, 19F and 3, accounting for 56.5% of all isolates (Table 1). Serotype 6B and 23F were the most frequently identified serotype from sterile sites in patients <5 and ≥65 years old. The serotype coverage of vaccines is shown in Table 2. PCV7 covered 70.3%, 43.6%, and 43.5% of S. pneumoniae isolates from sterile sites in patients <5 years, 5–64 years, and ≥65 years old, respectively. PCV-13 provided coverage to 81.2%, 59.7%, and 60.9% of isolates from patients in these age groups, respectively. Other PCVs (PCV-9, PCV-10, PCV-11) had similar coverage as PCV-7 in patients <5 years old, but slightly increased coverage in patients 5–64 years and ≥65 years (range 43.5–52.2%). In children <5 years of age, PCV-7 and PCV-13 covered 61.9% and 76.2% of isolates from non-sterile sites, respectively. For the analysis in this study, we used meningitis criteria for S. pneumoniae isolates from CSF only, and non-meningitis criteria for those from other sites (Table 3). With this analysis strategy, we found the penicillin susceptibility rates in isolates from sterile sites were 93.8%, 88.7% and 95.7% in patients <5, 5–64 and ≥65 years old, respectively.
The corresponding percentages for cefotaxime susceptibility were 90.6%, 98.4% and 93.5%, respectively. In contrast, penicillinand cefotaxime-susceptibility rates in isolates from non-sterile sites in patients <5 years old using criteria for non-meningitis and with oral penicillin treatment were 26.2% and 78.6%, respectively. The MICs for all antibiotics tested in isolates from non-sterile sites were higher than those from sterile sites. Susceptibility to ofloxacin ranged 92.2–100%, and all isolates were susceptible to ciprofloxacin. PCV-7 covered 83% and 100% of penicillin and cefotaxime non-susceptible isolates, respectively, from sterile sites in patients <5 years old. We demonstrated comparison of penicillin susceptibility of isolates from sterile sites in <5 years old using the former and the newer criteria in Fig. 1. If we used the former criteria, only 28.1% would be penicillin-susceptible S. pneumoniae (PSSP). 4. Discussion Our study describes the serotype distribution and antimicrobial susceptibilities of invasive pneumococcal isolates collected in Thailand from 2006 to 2009. Data on a small set of non-invasive isolates from children under five were also presented. Although this is a relatively small number of isolates from a limited geographic range, these results represent an important contribution, and presented several years of monitoring continuum from our previous report, to the very limited data on pneumococcal serotypes in this region. PCV-7 has been shown in many studies to be highly immunogenic and effective against IPD [5,15–17], with the vaccine efficacy of 97.4% against vaccine serotypes in the US [5]. In the large trial in South Africa and Gambia, the efficacy of PCV-9 was 83% and 77% against IPD caused by vaccine serotypes [18,19]. Twice as many IPD cases were indirectly prevented due to herd immunity after the PCV-7 implementation in the US [8]. Due to serotype specific effi-
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Table 3 Percentage of S. pneumoniae isolates sensitive to antibiotic drugs using the new Clinical Laboratory Standards Institute criteria, Thailand, 2006–2009. Drugs
<5 years old
Penicillin Cefotaxime Ofloxacin Ciprofloxacin
≥65 years old
5–64 years old
a
Sterile sites (n = 64)
Non-sterile sites (n = 42)
Sterile sites (n = 62)
Sterile sitesa (n = 46)
% susceptable
% susceptable
% susceptable
% susceptable
93.8 90.6 92.2 100
b
MICs (g/ml) MIC50
MIC90
0.25 0.25 2 0.5
2 1 2 1
26.2 78.6 100 100
a
MICs (g/ml) MIC50
MIC90
2 0.5 2 1
4 2 2 2
88.7 98.4 96.8 100
MICs (g/ml) MIC50
MIC90
0.5 0.06 1 1
2 0.5 2 2
95.7 93.5 93.5 100
MICs (g/ml) MIC50
MIC90
0.125 0.125 2 0.5
2 2 2 2
MIC50 and MIC90 are the minimal inhibitory concentration required to inhibit the growth of 50% and 90% of pneumococci, respectively. a The MIC breakpoints used for isolates from sterile sites based on criteria for meningitis if isolates were from CSF, and criteria for non-meningitis disease with intravenous penicillin for isolates from other sterile sites. b The MIC breakpoints used for isolates from non-sterile site based on the criteria for non-meningitis disease with oral penicillin.
cacy of the vaccine, serotype coverage of IPD implies and predicts the efficacy of the vaccine. In this region, the serotype coverage of 70.3% by PCV-7 in IPD in children under five years of age in our study was less than the 78% coverage found in Singapore [15], but higher than in a study in China in 2008 which found 63.6%, 64.8% and 79.6% coverage by PCV-7, PCV-10 and PCV-13, respectively [20]. The serotype coverage of IPD isolates by PCV-7 in children ≤14 years old in Taiwan was 85%, somewhat higher than in our study [21]. WHO reported the overall serotype coverage of PCV-7 ranged from 60 to 85% worldwide [22]. There has been a concern about the increased proportion of nonvaccine serotypes reported in the US and Spain after introduction of PCV-7 vaccination program [8,23,24]. The widely use of PCV-7 may contributed to the emergence of nonvaccine serotypes, especially serotype 19A [8,23,24]. However, a study in Korea reported an increase in serotype 19A even before the introduction of PCV-7 [25]. It is probable that both selective vaccine pressure and clonal spread were contributing factors to the circulating serotypes in the community. In Thailand, we reported the serotype coverage of PCV-7, PCV-9, PCV-11, and PCV-13 of 73.9%, 77.4%, 77.4%, and 87.8%, respectively, in children younger than 5 years of age during 2001–2005 [11]. The serotype coverage found in this study was somewhat lower than that report, but was still within the 95% confidential interval. Although PCV-7 has been available in Thailand since June 2006, the vaccine has been used mainly in private set-
Fig. 1. Penicillin susceptibility of S. pneumoniae isolated from sterile sites in children <5 years old using former and new CLSI criteria, Thailand, 2006–2009. Former criteria: susceptible, intermediate, and resistant MIC for penicillin were ≤0.06, 0.12–1, and ≥2 g/ml, respectively, for all pneumococcal isolates, regardless of clinical syndrome or route of penicillin administration. New criteria: susceptible and resistant MIC are ≤0.06 and ≥0.12 g/ml, respectively, for meningitis with intravenous penicillin; and susceptible, intermediate and resistant MIC are ≤2, 4, and ≥8 g/ml, respectively, for nonmeningitis with intravenous penicillin. The non-meningitis criteria was used for S. pneumoniae isolated from blood, and meningitis criteria was used for CSF.
tings with an estimated 55,000 doses sold each year, representing less than 5% of children <5 years of age. This low vaccine uptake did not seem to affect the serotype distribution in this relatively small study. The top seven serotypes of invasive isolates found in our study were different in rank of order and frequency (%) in each age groups, as well as whether the sites were sterile or non-sterile. Although the top seven serotypes of isolates from sterile sites in children younger than 5 years of age were not completely match with other studies reported earlier in Thailand [11,26–28], they were quite consistent. The common serotypes found in those and our studies were 6B, 14, 19A, 19F, 23F. The PCV that included all these serotypes, i.e. PCV-13, would be the most appropriate for large scale use in Thailand. The presence of cefotaxime-non-susceptible isolates from sterile sites, although few, are of concern because cefotaxime has been the main antibiotic used for treatment of pneumococcal meningitis. Currently, cefotaxime combine with vancomycin have been recommended as empirical treatment in meningitis until the susceptibility become available. The first clinical isolate that was highly resistant to ciprofloxacin (MIC > 32 g/ml) and other newer fluoroquinolones was reported in 1999 [29]. However, the reported prevalence of resistance to fluoroquinolones is relatively low (typically <0.5%) [30], and we found similar results in this study. The new criteria for penicillin susceptibility has increased the percentage of penicillin susceptible in non-meningitis isolates from sterile site treated with parenteral penicillin, and was more correlate with the clinical use [13]. Interpretation in the patients with clinical meningitis, of whom the organism was isolated out from blood only, should use the breakpoint for meningitis in such isolates. Due to the lack of clinical information in this study, we used the meningitis criteria only for CSF isolates, and non-menigitis criteria for all blood isolates, and therefore may have resulted in overestimation of penicillin susceptibility in some meningitis cases. However, the impact from this should be minimal as penicillin is not currently recommended for empirical treatment of meningitis. We found low rates of penicillin non-susceptibility of 4–11% in isolates from sterile sites of all age, but very high rate of 73.8% among isolates from non-sterile sites in young children. This latter information is of concern because it increased from 63% in 1997–1998 in our institution [31], to 69% in the year 2004–2005 [32], using the same cut-off levels. The MIC50 and MIC90 increased from 0.5 and 2 g/ml in 1997–1998 to 2 and 4 g/ml, respectively, in 2006–2009. Of note was that the MIC50 and MIC90 of isolates from sterile sites were unchanged over the time. These results needed to be communicated to clinicians for appropriate and judicious antibiotic therapy. The limitations of this study included a potential limited geographic representative; the isolates were mainly from central Thailand, and the relatively small numbers of total isolates. The lack of information on geographic distribution of PCV-7 uptake, partic-
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ularly with overall low uptake rate, made it impossible to evaluate any impact of the vaccine. In conclusion, this study found that the serotype distribution and coverage of all PCVs for S. pneumoniae in Thailand remain unchanged since the vaccine has been available in 2006. The licensing process of PCV-10 and PCV-13 in Thailand are in progress, and this study provides basic information to support the evaluation and impact of other PCVs in the future. Continued surveillance for pneumococcal serotypes and susceptibilities are crucial to provide information on emerging pneumococcal serotypes and the optimal composition of future conjugate vaccines as well as the impact of the vaccine after wide-spread use. Moreover, antimicrobial susceptibility can inform guidelines for selection of appropriate drugs for treatment of pneumococcal infections. Acknowledgements This work was funded by Wyeth-Ayerst (Thailand) Ltd. and in part by the Faculty of Medicine Siriraj Hospital, Mahidol University. We thank the following hospitals for supplying pneumococcal isolates: Bangkok Hospital, Bhummipol Hospital, Bumrungrad International Hospital, Chaophya Hospital, King Chulalongkorn Memorial Hospital, Mongkutwattana General Hospital, Phayathai Hospital, Queen Sirikit National Institute of Child Heath, Nakorn Pratom Hospital, Rajavithi Hospital, Ramkhamhaeng Hospital, Somdejprapinklao Hospital and Taksin Hospital. We thank Dr. Michelle McConnell for her critical inputs and helps to this manuscript. References [1] Obaro SK, Monteil MA, Henderson DC. The pneumococcal problem. BMJ 1996;312(7045):1521–5. [2] O’Brien KL, Wolfson LJ, Watt JP, Henkle E, Deloria-Knoll M, McCall N, et al. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 2009;374(9693):893–902. [3] Henrichsen J. Six newly recognized types of Streptococcus pneumoniae. J Clin Microbiol 1995;33(10):2759–62. [4] Park IH, Pritchard DG, Cartee R, Brandao A, Brandileone MC, Nahm MH. Discovery of a new capsular serotype (6C) within serogroup 6 of Streptococcus pneumoniae. J Clin Microbiol 2007;45(4):1225–33. [5] Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000;19(3):187–95. [6] American Academy of Pediatrics. Committee on Infectious Diseases. Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics 2000;106(2 (Pt 1)):362–6. [7] Ruckinger S, van der Linden M, Reinert RR, von Kries R, Burckhardt F, Siedler A. Reduction in the incidence of invasive pneumococcal disease after general vaccination with 7-valent pneumococcal conjugate vaccine in Germany. Vaccine 2009;27(31):4136–41. [8] Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease—United States, 1998–2003. MMWR Morb Mortal Wkly Rep 2005;54(36):893–7. [9] McBean AM, Park YT, Caldwell D, Yu X. Declining invasive pneumococcal disease in the U.S. elderly. Vaccine 2005;23(48–49):5641–5. [10] Lexau CA, Lynfield R, Danila R, Pilishvili T, Facklam R, Farley MM, et al. Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine. JAMA 2005;294(16):2043–51.
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