Vaccine Reports

Impact of the Seven-valent Pneumococcal Conjugate Vaccine on Acute Otitis Media in Japanese Children Emergence of Serotype 15A Multidrug-resistant Streptococcus pneumoniae in Middle Ear Fluid Isolates Daiki Ozawa, MD,*† Hisakazu Yano, MD, PhD,†‡ Shiro Endo, MD, PhD,† Hiroshi Hidaka, MD, PhD,* Risako Kakuta, MD,*† Naohiro Okitsu, MD, PhD,* Hajime Kanamori, MD, PhD,† Miho Ogawa,§ Sadahiro Ichimura,§ Masahiro Shimojima,§ Shinya Inomata, MD,† Mitsuo Kaku, MD, PhD,† and Yukio Katori, MD, PhD* Background: Streptococcus pneumoniae is one of the most common bacteria causing acute otitis media (AOM). In Japan, a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced for voluntary vaccination of children in 2010, and it became a recommended vaccination in April 2013. We surveyed the serotypes and antimicrobial susceptibility profile of S. pneumoniae isolates obtained from the middle ear fluid of Japanese children with AOM. Methods: Between April and September 2013, a total of 176 S. pneumoniae isolates were obtained from the middle ear fluid of children aged 0–3 years with AOM. Isolates were collected from various regions of Japan. Minimum inhibitory concentrations were measured by the broth microdilution method. Serotyping was performed by observing the Quellung reaction. Results: Although 45.5% of the strains were susceptible to penicillin G, 42.6% were penicillin-intermediate strains and 11.9% were penicillinresistant strains. Serotype 19A (27.3%), serotype 15A (14.2%) and serotype 3 (11.9%) showed a high frequency. Although PCV7 types only accounted for 4.5% of all strains, 44.9% were PCV13 types and 55.1% were non-PCV types. Serotype 15A strains were 100% nonsusceptible to penicillin G and all of these strains showed multidrug resistance. Serotype 15A was frequent in children up to 1 year old. Conclusion: After this research was completed, PCV7 was switched to a PCV13 that also contained serotype 3 and serotype 19A. We need to consider the possibility that serotype 15A, which is not included in PCV13, may increase and cause intractable AOM in the future. Key Words: Streptococcus pneumoniae, acute otitis media, 7-valent pneumococcal conjugate vaccine, serotype replacement, antimicrobial susceptibility (Pediatr Infect Dis J 2015;34:e217–e221)

S

treptococcus pneumoniae is one of the most common bacteria causing acute otitis media (AOM). Pathogenic bacteria are isolated from the middle ear fluid in up to 70% of patients with AOM, Accepted for publication February 22, 2015. From the*Department of Otolaryngology-Head and Neck Surgery, and †Department of Infection Control and Laboratory Diagnostics, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; ‡Department of Microbiology and Infectious Diseases, Nara Medical University, Kashihara, Nara, Japan; and §Department of Bacteriology, BML Inc., Kawagoe, Saitama, Japan. The authors have no conflicts of interest or funding to disclose. Address of correspondence: Daiki Ozawa, MD, Department of OtolaryngologyHead and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan. E-mail: daiki-oz@med. tohoku.ac.jp. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3409-e217 DOI: 10.1097/INF.0000000000000776

and 50% of confirmed bacterial infections are caused by S. pneumoniae.1 AOM is very common during the first 2 years of life, with the cumulative incidence of a first episode of AOM up to 12 months of age being reported as 42.4%, rising to 71.0% by 24 months.2 In the US, a pediatric 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2001. There have been reports that PCV7 decreases the incidence of invasive pneumococcal disease (IPD), including meningitis, sepsis and pneumonia.3 With regard to AOM, the Northern California Kaiser Permanente Trial showed a 7% decrease of total AOM episodes in the vaccinated group, whereas the Finnish Otitis Media Vaccine Trial found a decrease of 6%.4,5 The Finnish Otitis Media Vaccine Trial also showed that placement of tympanostomy tubes in children was reduced by 39% after introduction of PCV7.6 Thus, PCV7 had a considerable impact on intractable otitis media. PCV7 has been widely adopted around the world, but serotype replacement of S. pneumoniae has occurred within a few years of its introduction.3,7 To cope with the increase of nonvaccine type S. pneumoniae because of serotype replacement, a second-generation vaccine (PCV13) was developed and introduced in the US in 2010. In Japan, PCV7 was introduced as a voluntary vaccination for infants and children in 2010, and it became a recommended vaccination in April 2013. In November 2013, PCV7 was switched to PCV13. Thus, PCV7 was only used for 3 years in Japan compared with 10 years in the US before being replaced by PCV13, which means that there have been few reports about the impact of PCV7 on AOM in Japan. In this study, we surveyed the serotypes and antimicrobial susceptibility profile of S. pneumoniae isolates obtained from the middle ear fluid of children with AOM during the period when PCV7 was used for vaccination in Japan. The objectives of this study were to assess whether serotype replacement of S. pneumoniae occurred in Japanese children with AOM after introduction of PCV7 and compare the findings with those from other countries, as well as predicting serotype replacement in AOM patients after the introduction of PCV13.

MATERIALS AND METHODS Between April and September 2013, a total of 176 consecutive and nonduplicate clinical isolates of S. pneumoniae were obtained from the middle ear fluid of children. A requirement of isolates was specimens obtained from children diagnosed with AOM aged 0–3 years. All specimens were obtained with a sterile cotton swab from 86 otorhinolaryngology clinics in 7 regions covering all of Japan (Hokkaido-Tohoku region, population 14 million; Kanto region, population 42 million; Chubu region, population 23 million; Kinki region, population 22 million; Chugoku region,

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TABLE 1.  Background of the 176 Streptococcus pneumoniae Isolates Background Factor

n (%)

Sex  Male  Female Age  0 yr  1 yr  2 yr  3 yr Region  Hokkaido-Tohoku  Kanto  Chubu  Kinki  Chugoku  Shikoku  Kyushu

90 (51.1) 86 (48.9) 40 (22.7) 95 (54.0) 20 (11.4) 21 (11.9) 21 (11.9) 30 (17.0) 13 (7.4) 5 (2.8) 42 (23.9) 8 (4.6) 57 (32.4)

population 7 million; Shikoku region, population 3 million; Kyushu region, population 14 million; Table 1). Each sample was plated onto sheep blood agar and chocolate agar, after which the plates were incubated at 35°C for 18–24 hours under 5% CO2. Alpha-hemolytic colonies were selected and transferred to sheep blood agar, with S. pneumoniae being identified on the basis of sensitivity to optochin and bile solubility. Minimum inhibitory concentrations (MIC) were measured by the broth microdilution method according to the Clinical and Laboratory Standards Institute (CLSI) guidelines.8 The following antimicrobial agents were tested: penicillin G (PCG), ampicillin (ABPC), ceftriaxone (CTRX), cefditoren (CDTR), meropenem (MEPM), tebipenem (TBPM), levofloxacin (LVFX), tosufloxacin (TFLX), tetracycline (TC), erythromycin (EM), clindamycin (CLDM), trimethoprim-sulfamethoxazole (ST) and vancomycin (VCM). Susceptibility of S. pneumoniae to these antimicrobial agents was classified in accordance with the CLSI breakpoint criteria: susceptible (S), intermediate (I), resistant (R). Susceptibility to penicillin was classified according to the CLSI pre-2008 penicillin susceptibility breakpoint criteria, with the strains being classified as penicillin-susceptible S. pneumoniae (PSSP), penicillin-intermediate S. pneumoniae (PISP) or penicillin-resistant S. pneumoniae (PRSP). Note that there are no breakpoint criteria in the CLSI guideline for CDTR, TBPM and TFLX.8

Serotyping was performed by observing the Quellung reaction in the presence of antisera purchased from the Statens Serum Institut (Copenhagen, Denmark). S. pneumoniae have more than 90 serotypes, which are divided into 46 serogroups. In this study, serogroups that did not include PCV serotypes were generally just classified at the serogroup level, but serogroup 15 was classified at the serotype level because it showed a high frequency among non-PCV types.

RESULTS Assessment of PCG susceptibility showed that the prevalence rate of PSSP was 45.5%, followed by PISP at 42.6% and PRSP at 11.9%. In the case of ABPC, 42.0% of the strains were susceptible, 35.8% were intermediate and 22.2% were resistant. When CTRX, MEPM, LVFX and VCM were tested, over 90% of S. pneumoniae strains were susceptible (CTRX, 95.4%; MEPM, 90.9%; LVFX, 100%; VCM, 100%). In contrast, there were high prevalence rates of strains that were nonsusceptible to TC, EM and CLDM (TC, 92.0%; EM, 92.6%; CLDM, 76.7%). With regard to ST, 55.7% of the strains were nonsusceptible. The MIC50 of CDTR was 0.25 mg/L, and its MIC90 was 0.5 mg/L, whereas the MIC50 of TBPM was ≤0.03 mg/L, and its MIC90 was 0.06 mg/L. In addition, the MIC50 of TFLX was ≤0.125 mg/L, and its MIC90 was 0.25 mg/L (Table 2). The serotype distribution is shown in Figure 1. Serotype 19A (n = 48, 27.3%) showed the highest prevalence, followed by serotype 15A (n = 25, 14.2%) and serotype 3 (n = 21, 11.9%). PCV7 types were only found in 4.5% (n = 8), whereas PCV13 types accounted for 44.9% (n = 79) and non-PCV types amounted to 55.1% (n = 97). The serotype distribution of S. pneumoniae isolates is stratified by penicillin G susceptibility in Table 3. Among serotype 19A strains, 37.5% were PSSP, 47.9% were PISP and 14.6% were PRSP. Serotype 15A did not include PSSP, with 72.0% of strains being PISP and 28.0% being PRSP. All serotype 3 strains were PSSP and formed mucoid colonies. As mentioned previously, serotype 15A was 100% nonsusceptible to PCG. In addition, serotype 15A was 96.0% nonsusceptible to ABPC, 100% nonsusceptible to TC, 100% nonsusceptible to EM, 96.0% nonsusceptible to CLDM and 96.0% nonsusceptible to ST (Table 4). In 0-year-old patients, investigation of the serotype distribution revealed that 37.5% of strains were serotype 19A, 12.5% were serotype 15A and 7.5% were serotype 3. The prevalence of serotype 3 increased as the patients became older. In 3-year-old patients, the

TABLE 2.  Drug Susceptibility Profile of 176 Streptococcus pneumoniae Isolates From Japanese Infants and Children With AOM Drug Penicillin G Ampicillin Ceftriaxone Cefditoren Meropenem Tebipenem Levofloxacin Tosufloxacin Tetracycline Erythromycin Clindamycin Trimethoprim-­ sulfamethoxazole Vancomycin

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MIC Range (mg/L)

MIC50 (mg/L)

≤0.03 to >8 ≤0.03 to >8 ≤0.06 to >8 ≤0.06 to >8 ≤0.03 to >4 ≤0.03 to >4 ≤0.125 to >16 ≤0.125 to >16 ≤0.5 to >16 ≤0.125 to >8 ≤0.125 to >8 ≤0.12/2.38 to >4/76

0.125 0.25 0.25 0.25 ≤0.03 ≤0.03 1 ≤0.125 >16 >8 >8 1/19

≤0.5 to >2

≤0.5

MIC90 (mg/L) 2 2 1 0.5 0.25 0.06 1 0.25 >16 >8 >8 2/38 ≤0.5

S (%)

I (%)

R (%)

45.5 42.0 95.4 — 90.9 — 100 — 8.0 7.4 23.3 44.3

42.6 35.8 2.3 — 8.0 — 0.0 — 6.2 5.1 2.3 48.3

11.9 22.2 2.3 — 1.1 — 0.0 — 85.8 87.5 74.4 7.4

100





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PCV7 and Acute Otits Media

FIGURE 1.  Serotypes of Streptococcus pneumoniae isolated from the middle ear fluid of Japanese children with acute otitis media (n = 176). TABLE 3.  Serotype Distribution of Streptococcus pneumoniae Isolates Stratified by Penicillin G Susceptibility Serotype 19A 15A 3 6C 15C 29/34/35/42/47 11 15B 23A/B 19F 10 24/31/41 22 Nontypeable 6A 6B 6D 33 23F Total

n

PSSP (%)

PISP (%)

PRSP (%)

48 25 21 12 11 9 8 7 7 5 4 4 3 3 2 2 2 2 1 176

37.5 0.0 100 16.7 81.8 33.3 87.5 85.7 0.0 0.0 75.0 100 100 33.3 0.0 50.0 0.0 100 0.0 45.5

47.9 72.0 0.0 83.3 18.2 55.6 12.5 14.3 100 80.0 0.0 0.0 0.0 66.7 0.0 50.0 0.0 0.0 100 42.6

14.6 28.0 0.0 0.0 0.0 11.1 0.0 0.0 0.0 20.0 25.0 0.0 0.0 0.0 100 0.0 100 0.0 0.0 11.9

prevalence of serotype 3 reached 38.1% and it became the most frequent serotype causing AOM in that age group (Table 5).

DISCUSSION The incidence of AOM has increased recently in Japan, and many children now require hospitalization for intravenous

antibiotics to treat intractable otitis media with persistent purulent otorrhea.9,10 According to our previous study, the prevalence of PRSP ranged between 30.4% and 47.8% in Japanese children with AOM aged 0–2 years from 2001 to 2009,11 and a recent increase of PRSP has been reported as a major problem in relation to the treatment of AOM.12 In this study, the prevalence of PRSP was 11.9%. It has been reported that introduction of PCV7 leads to a decrease of PRSP,7 so the low prevalence of PRSP in this study may be attributed to introduction of PCV7 to Japan in 2010. In this study, we surveyed susceptibility to TBPM and TFLX. TBPM is an oral carbapenem that was approved in 2009, whereas TFLX is an oral fluoroquinolone approved in 2010. Both drugs have been recently prescribed in Japan for children with AOM. Although there are no breakpoint criteria for TBPM and TFLX in the CLSI guideline, S. pneumoniae shows good susceptibility to both drugs on the basis of MIC50 and MIC90 values. Because overuse of TBPM and TFLX may reduce susceptibility to carbapenems and fluoroquinolones, these drugs are not recommended for first-line treatment in clinical practice guidelines on the diagnosis and management of pediatric AOM in Japan, and we have to pay attention to appropriate prescription of these agents.13 In patients with IPD, replacement of other serotypes by serotype 19A is becoming a major problem since the introduction of PCV7.3,7 In the case of AOM, similar serotype replacement by serotype 19A has been reported.14–17 The serotype that follows next in prevalence after serotype 19A has varied in past reports. Casey et al14 reported that serotypes 6A and 6C followed next after serotype 19A in the US, Dupont et al15 reported that serotype 19F came after 19A in France and Gene et al16 reported that serotype 14 was next after 19A in Spain. In Greece, serotype 19F follows serotype 19A according to Stamboulidis et al.17 This

TABLE 4.  Drug Susceptibility Profile of serotype 15A Streptococcus pneumoniae Isolates From Japanese Children With AOM (n = 25) Drug Penicillin G Ampicillin Ceftriaxone Cefditoren Meropenem Tebipenem Levofloxacin Tosufloxacin Tetracycline Erythromycin Clindamycin Trimethoprimsulfamethoxazole Vancomycin

MIC Range (mg/L)

MIC50 (mg/L)

MIC90 (mg/L)

S (%)

I (%)

R (%)

≤0.03 to >8 ≤0.03 to >8 ≤0.06 to >8 ≤0.06 to >8 ≤0.03 to >4 ≤0.03 to >4 ≤0.125 to >16 ≤0.125 to >16 ≤0.5 to >16 ≤0.125 to >8 ≤0.125 to >8 ≤0.12/2.38 to >4/76

1 2 0.5 0.25 0.25 0.06 1 ≤0.125 >16 >8 >8 1/19

2 4 2 1 0.25 0.06 1 0.25 >16 >8 >8 1/19

0.0 4.0 88.0 — 92.0 — 100 — 0.0 0.0 4.0 4.0

72.0 44.0 8.0 — 8.0 — 0.0 — 0.0 4.0 8.0 96.0

28.0 52.0 4.0 — 0.0 — 0.0 — 100 96.0 88.0 0.0

≤0.5 to >2

≤0.5

≤0.5

100





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TABLE 5.  Serotype Distribution of 176 Streptococcus pneumoniae Isolates Stratified According to Patient Age

19A 15A 3 6C 15C 29/34/35/42/47 11 15B 23A/B 19F 10 24/31/41 22 Nontypeable 6A 6B 6D 33 23F

All Ages (%)

0 yr (%)

1 yr (%)

2 yr (%)

3 yr (%)

27.3 14.2 11.9 6.8 6.3 5.1 4.5 4.0 4.0 2.8 2.3 2.3 1.7 1.7 1.1 1.1 1.1 1.1 0.6

37.5 12.5 7.5 0.0 2.5 5.0 5.0 5.0 0.0 7.5 2.5 0.0 2.5 2.5 2.5 2.5 0.0 5.0 0.0

23.2 17.9 6.3 9.5 8.4 5.3 5.3 4.2 7.4 2.1 1.1 3.2 1.1 2.1 1.1 0.0 1.1 0.0 1.1

30.0 10.0 20.0 15.0 0.0 5.0 0.0 5.0 0.0 0.0 5.0 5.0 5.0 0.0 0.0 0.0 0.0 0.0 0.0

23.8 4.8 38.1 0.0 9.5 4.8 4.8 0.0 0.0 0.0 4.8 0.0 0.0 0.0 0.0 4.8 4.8 0.0 0.0

study showed that serotype 19A was the most frequent serotype and serotype 15A came next. Before the introduction of PCV7, serogroup 15 was highly prevalent in Japan following the PCV7 types (6B, 19F and 23F) and the PCV7 cross-reacting type (6A).18 Serotype 15A is not a PCV7 type, so a decline of PCV7 types after introduction of PCV7 may have led to the high position of serotype 15A in our study. According to Japanese clinical practice guidelines and the American Academy of Pediatrics guideline, penicillins are recommended as a first-line treatment for AOM.13,19 However, we found that all strains of serotype 15A isolated from Japanese children with AOM were nonsusceptible to PCG. In fact, all serotype 15A strains were nonsusceptible to at least 3 drug classes and were classified as multidrug-resistant S. pneumoniae.7 In this study, serotype 15A was frequently found in children from 0 to 1 year old. It is known that intractable AOM tends to occur in children younger than 2 years.20 Accordingly, we should recognize that a high prevalence of serotype 15A multidrug-resistant S. pneumoniae in 0-year to 1-year-old children with AOM may be an important risk factor for intractable AOM. In addition, this study identified a high prevalence of serotype 3 in children aged 2–3 years. Serotype 3 forms mucoid colonies and causes severe AOM with aggravation of hearing problems,21 so we should keep this serotype in mind when treating AOM in children over 2 years old. After this research was completed, the vaccine used in Japan was switched from PCV7 to PCV13, which also contains serotype 3 and serotype 19A. In IPD patients from the US, a decrease of serotype 3 and serotype 19A was reported after introduction of PCV13.22 Although we cannot predict whether the same decrease will occur in patients with AOM, if serotype 3 and serotype 19A decline among AOM patients after introduction of PCV13, we will need to pay attention to the possibility of an increase in serotype 15A which was not included in PCV13. In fact, there is a report from the US that serogroup 15 increased in nasopharyngeal colonization of AOM children after introduction of PCV13.23 It is known that AOM shows a relationship with nasopharyngeal colonization.24,25 So, an increment of serogroup 15 in nasopharyngeal colonization suggest an increment of AOM caused by serogroup 15. An increase in the prevalence of serotype 15A would lead to an increment of multidrug-resistant S. pneumoniae causing intractable

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AOM. Therefore, it is important to continue performing surveys to detect changes in the serotypes of S. pneumoniae associated with AOM in Japanese children, particularly the pattern of serotype replacement after introduction of PCV13.

ACKNOWLEDGMENTS This work was supported by Japan Society for the Promotion of Science KAKENHI Grant Number 26462546. REFERENCES 1. Taylor S, Marchisio P, Vergison A, et al. Impact of pneumococcal conjugate vaccination on otitis media: a systematic review. Clin Infect Dis. 2012;54:1765–1773. 2. Alho OP, Koivu M, Sorri M, et al. The occurrence of acute otitis media in infants. A life-table analysis. Int J Pediatr Otorhinolaryngol. 1991;21:7–14. 3. Hicks LA, Harrison LH, Flannery B, et al. Incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998-2004. J Infect Dis. 2007;196:1346–1354. 4. Black S, Shinefield H, Fireman B, 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;19:187–195. 5. Eskola J, Kilpi T, Palmu A, et al; Finnish Otitis Media Study Group. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001;344:403–409. 6. Palmu AA, Verho J, Jokinen J, et al. The seven-valent pneumococcal conjugate vaccine reduces tympanostomy tube placement in children. Pediatr Infect Dis J. 2004;23:732–738. 7. Kyaw MH, Lynfield R, Schaffner W, et al; Active Bacterial Core Surveillance of the Emerging Infections Program Network. Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae. N Engl J Med. 2006;354:1455–1463. 8. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically: Approved Standard-Seventh Edition M7–A7. Wayne, PA: CLSI; 2006. 9. Yano H, Suetake M, Kuga A, et al. Pulsed-field gel electrophoresis analysis of nasopharyngeal flora in children attending a day care center. J Clin Microbiol. 2000;38:625–629. 10. Yano H, Yamazaki Y, Qin L, et al. Improvement rate of acute otitis media caused by Haemophilus influenzae at 1 week is significantly associated with time to recovery. J Clin Microbiol. 2013;51:3542–3546. 11. Ozawa D, Yano H, Hidaka H, et al. Twelve-year survey (2001-2012) of the antimicrobial susceptibility of Streptococcus pneumoniae isolates

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from otorhinolaryngology clinics in Miyagi Prefecture, Japan. J Infect Chemother. 2014;20:702–708. 12. Tajima T, Sato Y, Toyonaga Y, et al. Nationwide survey of the development of drug-resistant pathogens in the pediatric field in 2007 and 2010: drug sensitivity of Streptococcus pneumoniae in Japan (second report). J Infect Chemother. 2013;19:510–516. 13. Kitamura K, Iino Y, Kamide Y, et al. Clinical practice guidelines for the diagnosis and management of acute otitis media (AOM) in children in Japan - 2013 update. Auris Nasus Larynx. 2015;42:99–106. 14. Casey JR, Adlowitz DG, Pichichero ME. New patterns in the otopathogens causing acute otitis media six to eight years after introduction of pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2010;29:304–309. 15. Dupont D, Mahjoub-Messai F, François M, et al. Evolving microbiology of complicated acute otitis media before and after introduction of the pneumococcal conjugate vaccine in France. Diagn Microbiol Infect Dis. 2010;68:89–92. 16. Gene A, del Amo E, Iñigo M, et al. Pneumococcal serotypes causing acute otitis media among children in Barcelona (1992-2011): emergence of the multiresistant clone ST320 of serotype 19A. Pediatr Infect Dis J. 2013;32:e128–e133. 17. Stamboulidis K, Chatzaki D, Poulakou G, et al. The impact of the heptavalent pneumococcal conjugate vaccine on the epidemiology of acute otitis media complicated by otorrhea. Pediatr Infect Dis J. 2011;30:551–555.

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PCV7 and Acute Otits Media

18. Sunakawa K, Farrell DJ. Mechanisms, molecular and sero-epidemiology of antimicrobial resistance in bacterial respiratory pathogens isolated from Japanese children. Ann Clin Microbiol Antimicrob. 2007;6:7. 19. Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics. 2013;131:e964–e999. 20. Prellner K, Kalm O, Pedersen FK. Pneumococcal antibodies and complement during and after periods of recurrent otitis. Int J Pediatr Otorhinolaryngol. 1984;7:39–49. 21. Suetake M, Irimada M, Takahashi S et al. Acute otitis media due to mucoid type Streptococcus pneumoniae. Otol Jpn. 2000; 10: 89–94 (in Japanese). 22. Kaplan SL, Barson WJ, Lin PL, et al. Early trends for invasive pneumococcal infections in children after the introduction of the 13-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2013;32:203–207. 23. Martin JM, Hoberman A, Paradise JL, et al. Emergence of Streptococcus pneumoniae serogroups 15 and 35 in nasopharyngeal cultures from young children with acute otitis media. Pediatr Infect Dis J. 2014;33:e286–e290. 24. Sluijter M, Faden H, de Groot R, et al. Molecular characterization of pneumococcal nasopharynx isolates collected from children during their first 2 years of life. J Clin Microbiol. 1998;36:2248–2253. 25. Faden H, Duffy L, Wasielewski R, et al. Relationship between naso pharyngeal colonization and the development of otitis media in children. Tonawanda/Williamsville Pediatrics. J Infect Dis. 1997;175:1440–1445.

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Impact of the Seven-valent Pneumococcal Conjugate Vaccine on Acute Otitis Media in Japanese Children: Emergence of Serotype 15A Multidrug-resistant Streptococcus pneumoniae in Middle Ear Fluid Isolates.

Streptococcus pneumoniae is one of the most common bacteria causing acute otitis media (AOM). In Japan, a 7-valent pneumococcal conjugate vaccine (PCV...
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