J Infect Chemother xxx (2017) 1e12

Contents lists available at ScienceDirect

Journal of Infection and Chemotherapy

journal homepage: http://www.elsevier.com/locate/jic

Original Article

Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after

the wide use of Haemophilus influenzae type b and Streptococcus
pneumoniae conjugated vaccines*
Masayoshi Shinjoh a, b, *, Yoshio Yamaguchi c, Satoshi Iwata b, d
a
Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
b
Center for Infectious Diseases and Infection Control, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
c
Department of Clinical Research, National Hospital Organization, Tochigi Medical Center, 1-10-37 Nakatomatsuri, Utsunomiya-city, Tochigi, Japan
d
Department of Infectious Diseases, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Background: Haemophilus influenzae type b (Hib) vaccine and pneumococcal conjugated vaccine (PCV)
Received 15 January 2017 have been widely used since 2010 in Japan when both vaccines were supported by the regional gov-
Received in revised form ernments, and they were covered as routine recommended vaccines in 2013. The incidence of bacterial
22 February 2017
meningitis due to these organisms decreased in 2011 and 2012, but meningitis due to Streptococcus
Accepted 28 February 2017
Available online xxx
agalactiae and Escherichia coli remained unchanged.
Objectives: We planned to confirm whether the incidence also decreased in subsequent years.
Methods: We analyzed the epidemiological and clinical data for 2013e2015, and compared the infor-
Keywords:
Bacterial meningitis
mation obtained in the previous nationwide survey database and our previous reports. We also inves-
Children tigated the risk factors for disease outcome.
Haemophilus influenzae type b (Hib) vaccine Results: In the 2013e2015 surveys, 407 patients from 366 hospitals from all prefectures were evaluated.
Pneumococcal conjugated vaccine S. agalactiae (33%), Streptococcus pneumoniae (25%), and E. coli (10%) were the main organisms. The total
Streptococcus agalactiae number of patients hospitalized with bacterial meningitis per 1000 admissions decreased from 1.19 in
2009e2010 to 0.37 in 2013e2015 (p < 0.001). The incidence of H. influenzae and S. pneumoniae men-
ingitis significantly decreased from 0.66 in 2009e2010 to 0.01 in 2013e2015, and from 0.30 to 0.09,
respectively (p < 0.001). Only 0e2 cases with Neisseria meningitidis were reported each year throughout
2001e2015. The fatality rates for H. influenzae, S. pneumoniae, S. agalactiae, and E. coli in 2013e2015 were
0.0, 4.1, 3.1, and 2.6%, respectively. Risk factors for death and sequelae were consciousness disturbance,
convulsion, low CSF glucose, and Staphylococcus sp. as a causative organism (p < 0.01).
Conclusions: Hib vaccine and PCV have decreased the rate of bacterial meningitis. S. agalactiae has
subsequently become the most common cause of bacterial meningitis in Japan.
© 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.
Published by Elsevier Ltd. All rights reserved.

1. Introduction antimicrobial treatment. A nationwide annual surveillance ques-

Pediatric bacterial meningitis is a life-threatening emerging
disease, and neurologic sequelae are not uncommon despite
*
The departments and institutions to which the work is to be attributed:
Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi,
Shinjuku-ku, Tokyo 160-8582, Japan.
* Corresponding author. Department of Pediatrics, Keio University School of
Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Fax: þ81 3 5379
1978.
E-mail addresses: m-shinjo@z2.keio.jp (M. Shinjoh), yoyamaguchi@tochigi-mc.
jp (Y. Yamaguchi), siwata@a8.keio.jp (S. Iwata).
tionnaire for bacterial meningitis has been conducted from 1966 in
Japan by volunteer doctors [1e10]. Although there is a national
reporting system, only invasive diseases caused by Haemophilus
influenzae, Streptococcus pneumoniae, and Neisseria meningitidis
have been subject to mandatory reporting since 2013, 2013, and
1918, respectively [11]. The reporting of diseases caused by Strep-
tococcus agalactiae, Escherichia coli, and Listeria monocytogenes is
not required, and the clinical information obtained from this sys-
tem is minimal.
H. influenzae type b (Hib) vaccine (ActHIB®, Sanofi K.K. Japan)
and 7 valent pneumococcal conjugated vaccines (PCV 7) (Pre-
venar®, Pfeizer Japan Inc.) have been widely used since 2010 in

http://dx.doi.org/10.1016/j.jiac.2017.02.014
1341-321X/© 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Shinjoh M, et al., Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after the wide use of
Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines, J Infect Chemother (2017), http://dx.doi.org/10.1016/
j.jiac.2017.02.014
2 M. Shinjoh et al. / J Infect Chemother xxx (2017) 1e12
Japan. Hib and PCV 7 vaccines were partially supported by the
regional governments in November 2010 and were then covered as
routine recommended vaccines in April 2013 [12]. In November
2013, PCV 13 (Prevenar 13®, Pfeizer Japan Inc.) replaced PCV 7. The
incidence of bacterial meningitis due to these organisms showed a
decrease in 2011 and 2012, but meningitis due to S. agalactiae and
E. coli remained unchanged. The purpose of this study is to provide
an overview of recent trends in bacterial meningitis and the impact
of immunization with Hib vaccine and PCV in Japan. Here, we
present the surveillance questionnaire data, including the newly
obtained data from 2013 to 2015.
2. Patients and methods
A cross-sectional, multicenter, non-interventional study was
conducted in Japan in December 2015. Similar methods were used
as reported [10]. Questionnaires were sent to the same 517 hospi-
tals as in the 2011e2012 survey, including almost all university
hospitals, pediatric centers, and public hospitals with pediatric
admissions from all districts in Japan. The questionnaires included
questions on pediatric and neonatal bacterial meningitis reported
at each institute in 2013e2015. Bacterial meningitis was defined as
a systemic infection with positive bacterial culture or PCR in the
CSF, or pleocytosis in CSF with positive blood bacterial culture. The
annual number of new pediatric admissions at each institution was
recorded. The amount of Hib and PCV vaccines that were produced
(data from the Japanese Association of Vaccine Industries, Tokyo,
Japan), and the portal site of official statistics of Japan, “e-Stat” [13]
were used to estimate the coverage rate. We also used the database
that included information from previous, similar surveys that were
performed [1e10].
We reported the epidemiological data of pediatric bacterial
meningitis including the information on age, causative organisms,
antimicrobial resistance, used antibiotics, dexamethasone use,
compliance with Japanese guidelines, and prognosis. We also
calculated the case rates per 1000 pediatric admissions (total
number of meningitis patients/all pediatric admissions  1000)
instead of using a population-based method. All data were
collected from all areas of Japan, and the sample size was similar to
that of the survey of 2011e2012 [10] (Table 1).
Statistical analysis was performed by using SPSS 22.0 software
(IBM, US) or Ekuseru-Toukei 2015 for Windows software program
(Social Survey Research Information Co., Ltd., Tokyo, Japan).
P < 0.05 was considered statistically significant for all analyses,
including the risk factor analysis. To analyze the risk factors, binary
logistic methods were chosen. First we did a univariate analysis,
and the risk factors from the univariate analysis (P < 0.1) were put
in a multivariate analysis by the forced entry method. Dependent
valuables considered in the models were “poor outcome”
(including death, hearing loss, epilepsy, mental retardation, or
bedridden) but transient lesions such as subdural fluid collection
were included in “good outcome,” and the covariates (independent
valuables) were the same as previously reported items [10], “hos-
pital-acquired” and “Staphylococcus sp. (including Staphylococcus
aureus)” as a causative organism.
The study was approved by the Keio University Ethics Com-
mittee (No. 2011029).
3. Results
3.1. Epidemiology of bacterial meningitis in children in Japan
In the 2013e2015 surveys, there were 366 questionnaires
returned (366/517 [71%]), coming from the hospitals including 61%
of university hospitals in Japan (85/140) and 58% of non-university
Please cite this article in press as: Shinjoh M, et al., Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after the wide use of
Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines, J Infect Chemother (2017), http://dx.doi.org/10.1016/
j.jiac.2017.02.014
pediatric centers in Japan (15/26). The results revealed 407 (139,
124 and 139 for 2013, 2014 and 2015, and 5 for unknown year
between 2013 and 2015) patients with pediatric meningitis were
reported at 165 hospitals. The remaining 201 hospitals experienced
no meningitis cases. The new pediatric admissions at 366 hospitals
were approximately 360,000 each year (Table 1). Patients included
225 males and 178 females, and for 4 patients, the gender was not
reported. The age distribution is shown in Fig. 1. The patients'
median age was 3 months. There were 3.9% of patients (16/407)
who were immunocompromised. Underlying intracranial diseases
such as neurosurgery, head trauma, and ventricular shunt were
seen in 18% of patients (72/407) e 0% (0/12), 10% (10/101), 0% (0/
136), 5.1% (2/39), 65% (11/17), 81% (26/32), and 31.9% (22/69)
suffering from meningitis due to H. influenzae, S. pneumoniae,
S. agalactiae, E. coli, S. aureus, coagulase-negative Staphylococcus,
and others, respectively.
The causative organisms in 2013e2015 and the trends since
1966 are shown in Fig. 2a and b, respectively. S. agalactiae (33%)
were the most observed organisms, followed by S. pneumoniae
(25%) and E. coli (10%). H. influenzae had been the most common
between 1976 and 2011, but S. agalactiae took over that position.
The incidence rate per 1000 admissions (407 cases in 366 hos-
pitals) is shown in Table 1. The case rates for total and H. influenzae
meningitis were significantly lower in 2013e2015 compared to in
2009e2010 (1.20 to 0.38 and 0.66 to 0.01, p < 0.001), and 2011e2012
(0.55 to 0.38 and 0.19 to 0.01, p < 0.001), respectively. The rates for
S. pneumoniae was also lower in 2013e2015 compared to in
2009e2010 (0.30 to 0.09, p < 0.001), but not in 2011e2012 (0.11 to
0.09, p ¼ 0.22). The rate for S. agalactiae and E. coli remained un-
changed in 2013e2015 compared to in 2009e2010 (0.10 to 0.13 and
0.04 to 0.04, p ¼ 0.19 and p ¼ 0.82) and 2011e2012 (0.13 to 0.13 and
0.04 to 0.04, p ¼ 0.90 and p ¼ 0.83), respectively. Only 0e2 cases with
N. meningitidis were reported each year throughout 2001e2015.
3.2. H. influenzae and S. pneumoniae serotypes
Of the 12 patients with H. influenzae, 11 were serotyped and 6 of
the patients (55%) were confirmed as having the type b serotype
meningitis. Of these, only one patient (17%) had been vaccinated
(twice) but had no sequelae. One of the five unvaccinated Hib pa-
tients, who did not receive dexamethasone, had mild hearing loss.
Among five patients with non-Hib, two were non-typeable, and
three were unknown. All five had no sequelae.
Of the 101 patients with S. pneumoniae, 70 had information on
both serotypes and vaccine status (Table 2). Three patients were
immunized and five unimmunized out of eight patients with PCV
serotypes, while 50 patients were immunized and 12 unimmunized
out of 62 patients with non-PCV serotypes. Pneumococcal infection
related to PCV serotypes tended to be observed among PCV-
unvaccinated children (p ¼ 0.017). Serotype 15A (11 cases [18%]),
15B or C (9 [15%]), 24F (8 [13%]), and 35B (7 [11%]) were the most
observed among 62 cases with non-PCV serotypes. Two cases with
serotype 19A were observed in July 2013 (immunized with PCV 7
only), and February 2014 (non-immunized).
3.3. Penicillin susceptibility of H. influenzae and S. pneumoniae
(Table 1)
The H. influenzae ampicillin susceptibility did not change in
2013e2015 compared to in the era without Hib vaccine (5/12 [42%]
in 2013e2015 vs. 291/678 [43%] in 2001e2010; p ¼ 1.000, and vs.
59/115 [51%] in 2011e2012; p ¼ 0.53). The S. pneumoniae penicillin-
G susceptibility rate was higher in 2013e2015 compared to in the
era without PCV (64/97 [66%] in 2013e2015 vs. 82/249 [33%] in
2001e2010; p < 0.001, and 36/70 [51%] in 2011e2012, p ¼ 0.058).
 Table 1
j.jiac.2017.02.014
Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines, J Infect Chemother (2017), http://dx.doi.org/10.1016/
Please cite this article in press as: Shinjoh M, et al., Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after the wide use of

Trends in bacterial meningitis in Japan, 2001e2015.a

Year 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2013e15d

Number of hospitals answered 126 126 116 116 96 96 112 112 153 153 312 312 366 366 366 366
Total pediatric admissions 114,562 120,718 320,218 321,860 353,031 350,842 371,711 1,066,261
Hib vaccine produced (Liter) 462 1635 2539 2035 2375 2058 1919 6352
per 0e1 y/o infantsb 0.21 0.78 1.20 0.97 1.14 1.00 1.00
PCV produced (Liter) 166 1495 2134 2447 2320 2895 1627 6842
per 0e1 y/o infantsb 0.08 0.71 1.00 1.17 1.11 1.41 0.85
PCV13 produced (Liter) 0 0 0 0 1206 2895 1627 5728
PCV7 produced (Liter) 166 1495 2134 2447 1114 0 0
Total number of cases 93 150 90 122 116 113 135 141 149 153 207 150 139 124 139 407
(/1000 admissions) (1.16) (1.68) (1.00) (1.49) (1.61) (1.57) (1.45) (1.59) (1.23) (1.17) (0.64) (0.46) (0.39) (0.35) (0.37) (0.38)
(1.20) (0.55) (0.38)
H. influenzae 51 87 61 80 74 62 78 85 83 84 98 23 6 3 3 12
(/1000 admissions) (0.64) (0.98) (0.68) (0.98) (01.03) (0.86) (0.84) (0.96) (0.68) (0.64) (0.30) (0.07) (0.02) (0.01) (0.01) (0.01)
(0.66) (0.19) (0.01)
(%) (54.8) (58.0) (67.8) (65.6) (63.8) (54.9) (57.8) (60.3) (55.7) (54.9) (47.3) (15.3) (4.3) (2.4) (2.2) (2.9)
<5 years old NA NA NA NA 82 84 92 19 3 3 1 7
S. pneumoniae 20 36 14 24 20 28 29 25 34 42 36 38 30 33 37 101
(/1000 admissions) (0.25) (0.4) (0.16) (0.29) (0.28) (0.39) (0.31) (0.28) (0.28) (0.32) (0.11) (0.12) (0.08) (0.09) (0.1) (0.09)

M. Shinjoh et al. / J Infect Chemother xxx (2017) 1e12

(0.30) (0.11) (0.09)
(%) (21.5) (24.0) (15.6) (19.7) (17.2) (24.8) (21.5) (17.7) (22.8) (27.5) (17.4) (25.3) (21.6) (26.6) (26.6) (24.8)
<5 years old NA NA NA NA 32 40 29 30 23 21 24 69
S. agalactiae 8 10 6 7 11 8 13 13 14 10 37 47 44 41 48 136
(/1000 admissions) (0.1) (0.11) (0.07) (0.09) (0.15) (0.11) (0.14) (0.15) (0.12) (0.08) (0.11) (0.14) (0.12) (0.12) (0.13) (0.13)
(0.10) (0.13) (0.13)
(%) (8.6) (6.7) (6.7) (5.7) (9.5) (7.1) (9.6) (9.2) (9.4) (6.5) (17.9) (31.3) (31.7) (33.1) (34.5) (33.4)
E. coli 4 7 3 6 3 3 4 5 3 7 8 17 17 7 14 39
(/1000 admissions) (0.05) (0.08) (0.03) (0.07) (0.04) (0.04) (0.04) (0.06) (0.02) (0.05) (0.02) (0.05) (0.05) (0.02) (0.04) (0.04)
(0.04) (0.04) (0.04)
(%) (4.3) (4.7) (3.3) (4.9) (2.6) (2.7) (3.0) (3.5) (2.0) (4.6) (3.9) (11.3) (12.2) (5.6) (10.1) (9.6)
N. meningitidis 1 1 1 1 0 2 1 1 0 1 2
(/1000 admissions) (0.01) (0.00) (0.00) (0.00) (0.00) (0.00)
(%) (1.0) (0.7) (0.7) (0.0) (0.7) (0.5)
L. monocytogenes 2 or 3 1 1 2 3 2 2 7 0 4 11
(/1000 admissions) (0.01) (0.01) (0.02) (0.00) (0.01) (0.01)
(%) (1.0) (1.3) (5.0) (0.0) (2.9) (2.7)
S. pneumoniae (serotype known) NA NA NA NA NA 28 73
PCV7 strains (%) 11 (39.3) 3 (4.1)
PCV13 strains (%) 14 (50.0) 8 (11.0)
non-PCV strains (%) 14 (50.0) 65 (89.0)
Median age (months) and range
Total, median age 12 11 10 10 11 10 2 3 3 3 3
range 0M-16Y 0M-16Y 0M-15Y 0M-13Y 0M-18Y 0M-11Y 0M-15Y 0M-16Y 0M-15Y 0M-17Y 0M-17Y
H. influenzae, median age NA NA NA NA 14 13 46
range 1M-5Y 2M-10Y 2M-12Y
S. pneumoniae, median age NA NA NA NA 11 14 24
range 1M-12Y 1M-14Y 0M-15Y
S. agalactiae, median age NA NA NA NA 1 0 0
range 0-4M 0-10M 0-26M
E. coli, median age NA NA NA NA 0 0 1
range 0-3M 0-9M 0-9M
Penicillin Susceptibility ratec
H. influenzae, tested 44 76 53 74 69 59 72 78 73 80 93 22 6 3 3 12
susceptible 20 36 16 26 24 24 32 38 35 40 47 12 2 3 0 5
(Susceptibility rate %) (45.5) (47.4) (30.2) (35.1) (34.8) (40.7) (44.4) (48.7) (47.9) (50.0) (50.5) (54.5) (33.3) (100) (0.0) (41.7)
(42.9) (51.3) (41.7)
(continued on next page)

3
 4 M. Shinjoh et al. / J Infect Chemother xxx (2017) 1e12

3.4. Treatment
2013e15d

(66.0)
The national guidelines recommend that the initial antibiotics

(3.2)

(0.0)

(4.1)

(3.1)

(2.6)
279

131
97
64

12

98

38
should be treated separately and divided into neonates and others
9

1
[14]. The majority of patients <1 month old were initially treated
with ampicillin plus one of the cephalosporins ((70/109 [64.2%]),
(75.0)
2015

(0.0)

(0.0)

(0.0)

(0.0)

(0.0)
mostly cefotaxime); patients 1 month and older received one of the
36
27

91

36

38

14
0

3
0

0
carbapenems plus another beta-lactam (103/295 [34.9%]). As an

1.00 is the ideal number, as the number is calculated as “total vaccine doses/(population of 0 y/o x 3 þ population of 1 y/o x 1)” as 0 y/o receives 3 doses and 1 y/o receives one dose in Japan.
initial treatment, 38.6% (156/404) of the patients received carba-
(71.9)

penem (59 of panipenem, 94 of meropenem, and 3 of dripenem).

2014

(4.3)

(0.0)

(6.1)

(4.1)

(0.0)
32
23

92

33

49
All patients with H. influenzae (12 cases) used ceftriaxone (10) or
4

3
0

7
0
cefotaxime (2), with (3) or without (9) meropenem, ultimately. The
most frequently used final regimens for S. pneumoniae (93 cases
(48.3)
(66.0)
2013

(5.2)

(0.0)

(6.9)

(4.5)

(5.9)
were known) were ampicillin (26), cefotaxime (17), panipenem
29
14

96

29

44

17
5

6
0

1 (14), meropenem (8), and meropenem with cefotaxime (7). The

most frequently used carbapenems including combination therapy
for S. pneumoniae was panipenem (23). Approximately 85.7% (114/
(58.3)
2012

(2.5)

(0.0)

(0.0)

(4.3)

(6.3)

Ampicillin for H. influenzae (minimal inhibitory concentration, MIC 1 mg/ml is susceptible) and penicillin-G (MIC 0.06 mg/ml is susceptible) for S. pneumoniae.
120

133) of patients with S. agalactiae used ampicillin with (39) or

36
21

20

38

46

16
3

without (75) other agent. Of these, 19 cases used ampicillin with

cefotaxime, and 7 cases used ampicillin with gentamycin as final
(44.1)
(51.4)
2011

treatment. The compliance with the Japanese guidelines [14] in the

(3.5)

(2.1)

(6.1)

(5.6)

(0.0)
172
34
15

95

33

36
6

8
0

antimicrobial treatment are shown in Fig. 3. The points most

different from the Japanese guidelines for empiric treatment were
the use of three kinds of antibiotics for neonates (8/17), and peni-
(43.6)
2010

cillin plus cefotaxime or ceftriaxone for children 1 month and older

39
17

(15/30).
Of 169 patients who used dexamethasone, 163 patients had
(29.4)

information on the dose and duration. Roughly 73.6% of patients

2009

(1.1)

(1.2)

(0.0)

(4.2)

(0.0)
273

165
34
10

74

24

10

(120/163) used the standard dose and duration (0.15 [0.13e0.17]

3

mg/kg/dose, four times a day, for 2e4 days). Approximately 75% of

(43.5)
2008

patients with H. influenzae and S. pneumoniae used dexamethasone

23
10

(Fig. 4).
(28.0)
2007

(1.6)

(0.6)

(3.8)

(3.8)

(0.0)

3.5. Outcome
248

161
25

52

26
7

9
0

The patient fatality rates are shown in Table 1 and Fig. 5. The rate
(30.8)
2006

for S. pneumonia is the highest (4/98 [4.1%]) among the four major
26
8

organisms in 2013e2015, but lower than 5%. The serotype and

penicillin sensitivity for the death cases were 10A, 15B, 15C, and
(29.4)

(10.5)

unknown, and two susceptible and two resistant, respectively.

2005

(1.9)

(1.5)

(0.0)

(0.0)
208

135
17

48

19

Initial therapies for those cases were cefotaxime þ meropenem for

5

6
0

two cases, and cefotaxime þ vancomycin for one case, and un-
(17.4)

known for one case. The fatality rate for Staphylococcal meningitis
2004

The database of previous surveys for 2001e2012 [6e10] were included.

A total of 5 cases had no information on years between 2013 and 2015.

23

was 0.2% (1/46), but neurological sequelae were common (16/46

4

[35%]) (Table 3).

(38.5)
2003

(3.1)

(1.5)

(7.9)

(7.7)

(0.0)
196

136
13

38

13

3.6. Risk factors for death or sequelae

5

9
0
Patient fatality rate among cases with known outcome
(33.3)
2002

A comparison between patients who died or had sequelae

33
11

(N ¼ 93, 24%) and those with no sequelae (N ¼ 294, 76%) revealed

that hospital-acquired, consciousness disturbance, convulsions,
(31.3)
(32.9)
2001

low CSF glucose (<20 or <15 mg/dl), and Staphylococcus sp. (both
(1.9)

(0.6)

(3.1)

(8.7)

(0.0)
260

163
16

65

23
5

9
0

coagulase positive and negative) as causative organism were all

associated with death and sequelae (Table 3). A multivariate anal-
ysis yielded a significant coefficient of determination (p < 0.001 and
Nagelkerke R2 ¼ 0.253 using the forced entry method). However,
Total of 4 major organisms

the variable “hospital-acquired” was eliminated when the covariate

(Susceptibility rate %)

“Staphylococcus sp.” was inserted in the multivariate analysis (see

S. pneumoniae, tested

Table 3).
Table 1 (continued )

S. pneumoniae

NA, not analyzed.

H. influenzae
susceptible

S. agalactiae

4. Discussion
(rate %)

(rate %)

(rate %)

(rate %)

(rate %)
deaths

deaths

deaths

deaths

deaths
E. coli

We estimated that at least 30e40% of bacterial meningitis cases

Year

in children were included in our present study based on the

a
b
c
d

following three reasons. First, in our survey of bacterial meningitis

Please cite this article in press as: Shinjoh M, et al., Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after the wide use of
Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines, J Infect Chemother (2017), http://dx.doi.org/10.1016/
j.jiac.2017.02.014
 M. Shinjoh et al. / J Infect Chemother xxx (2017) 1e12 5

Fig. 1. Pediatric age distribution in bacterial meningitis, 2013-2015

a. Neonates (N ¼ 107)
b. <12 months (N ¼ 267)
c. Total (N ¼ 403).

in 2009e2010 [9], the reported cases were estimated to be 10% of
all cases with bacterial meningitis in Japan using the portal site of
the official statistics of Japan (e-stat [13]) and the official data of the
Ministry of Health, Labour and Welfare [15]. For the last study in
2011e2012 and the present study in 2013e2015, the number of
pediatric admissions increased threefold from the 2009e2010
survey. Second, we reported the cases with meningitis due to
H. influenzae and S. pneumoniae at a rate approximately 1.5 times
higher than Suga et al. [16,17] reported in 10 prefectures in 2013
(23% population of <5 years old, 1,181,000/5,239,000 [18]) (3 and 23
cases [Table 1] vs 2 and 13 cases [16,17] for children under 5 years
old, respectively). Third, the number of inpatients per day for 0e14
years in Japan in 2014 was 28,100 (¼10,256,500 per year) [19], and
new admissions were estimated to be 1/10 (1,025,650), because the
average length of hospital stay was approximately 10 days for this
age group [20]. New pediatric admissions in our study in 2014
(350,842, [Table 1]) represented around 35% of this value. However,
we estimated that more than 30e40% of cases were reported, as
60% of the university hospitals and pediatric centers returned the
questionnaire, institutions where more cases with meningitis
would typically be admitted.
The decreasing rate of bacterial meningitis due to H. influenzae,
S. pneumonia, and S. agalactiae is similar to the report of meningitis
in 10 prefectures [16,17]. They reported that the rate was 98%, 61%,
and 28% for H. influenzae, S. pneumonia, and S. agalactiae, respec-
tively between 2008 and 2010 and 2013. Our data showed the rate of
decrease rate was 98% (0.68e0.02), 70% (0.28e0.08), and 8%
(0.12e0.12) for H. influenzae, S. pneumonia, and S. agalactiae,
respectively, between 2009 and 2013 (Table 1). In the United States,
where the Hib vaccine was introduced in 1987, the incidence of
meningitis due to H. influenzae declined by 94% from 1986 to 1995
(2.9e0.2 cases per 100,000 population) [21]. Also in the United
States, where PCV 7 was introduced in 2000, the overall incidence of
pneumococcal meningitis in children <2 years old declined by 64.0%
from 1998e1999 to 2004e2005 [22]. The relative difference in
incidence is quite similar, although Japan is 20 years and 10 years
behind in terms of the introduction of Hib and pneumococcal vac-
cines, respectively. Invasive meningococcal meningitis is rare in all
age groups in Japan even after the introduction of Hib vaccine and
PCV in the present study. Also, the meningococcal vaccine is not
routinely used, as only 24 litters (48,000 doses) were distributed in
Japan in 2015 (data from Japanese Association of Vaccine Industries,

Please cite this article in press as: Shinjoh M, et al., Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after the wide use of
Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines, J Infect Chemother (2017), http://dx.doi.org/10.1016/
j.jiac.2017.02.014
6 M. Shinjoh et al. / J Infect Chemother xxx (2017) 1e12

b
100%
13 5
3.99 10 6 8 11 10
6.968 9.988 6.992 10.92 6 9 10 12 13 16
13 6 28 others
31 12.024 8.94 3 3 25
9.99 1.995 0 16 7 4 7
90% 21 55 0.988
50 10.99413.983 7 3 5 3
16 46 52 2.002 1 8 4 6 37
54 52 14.946 11 10
34 56 53 29 6.03 5.984 10 8 42
54 57 9 8 13 40
Frequency of idenficaon, %

21 4.02 6.006 13 14
80% 30 16 5 27 8
24 11.001 8
20 24.957 6.996
5.022 17
10.008 6.03 5 14 E. coli
4.02 24
37
32 25.992 20
70% 31 5.014 6.018 36
3.021 29 25 42 14
9 24 21 28
35 7.02 34
23 20 7
38 22 20 3.009 7.992 2.014 27.027 17
52 17 11 10.02 19.008 26
15 12.998 26
60%
5.98 Streptococcus
18
6 38 24 16.017 36 47
56 38 14 81
14 15
22 10.017
15 16 11 7.021
50% 9.99
11 13.983
9 18 34 5.014
19.008 41 48
24 42 30
32 5.015 44 S. agalacae
40% 39
22 41 36
43 37 18
5 50 61
4 6 80 74
15 8.024
30% 29 85
87 78
33 42.028 51 62 83 84 38
31 27 34.97446.024
33 45.045 51 S. pneumoniae
51 98
23.002 23.997
20% 38 18.998 21.978 20
13 26 22.007 79
66 66
11 22.968 33 37
15 59 30
46 49
15 63 57 47 24
42 13.983
10%
33 H. influenzae
16 23

4 15
2 5 6
1 1 2 3 3
0%
1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Fig. 2. Causative organisms of bacterial meningitis in children

a. 2013e2015, N ¼ 407
b. By year since 1966
Streptococcus, Streptococcus other than S. pneumoniae (1966e1978).

Table 2
S. pneumoniae and serotypinga (2013e2015).
Vaccinated with PCV
Unvaccinated with PCV
total
a
Of 101 patients with S. pneumoniae, 73 had information on serotypes, and 70
had information on both serotypes and vaccine status.
b
Serotypes 3, 19A (immunized with PCV 7 only) and 19F.
c
Serotypes 6A, 6B, 7F, 19A and 19F.
d
Serotypes 15A (11 cases, 18%), 15B or C (9, 15%), 24F (8, 13%) and 35B (7, 11%)
were most observed.
Tokyo, Japan). A national surveillance system also reported only
seven children (two children <5 years and five between 10 and 19)
suffered from invasive meningococcal disease between April 2013
and December 2014, although it is one of the diseases requiring
reporting in Japan [23].
Serotype replacement and change in susceptibility of
H. influenzae and S. pneumoniae is a great concern of pediatricians.
Hoshino et al. [24] reported that a shift from Hib to non-typeable
H. influenzae and encapsulated strains other than Hib (non-b),
particularly serotypes a, e, and f (Hif), has been observed after the
introduction of the Hib vaccine in other countries, and all three of
the Hif strains isolated in Japan in their study were classified as
ST124, which is a predominant invasive Hif strain in many countries
PCV meningitis Non-PCV meningitis total [24]. Japan has not been faced with a risk as of yet, but it will be
3b 50 53
necessary to monitor the possibility of seroreplacement with non-b
5c 12 17 H. influenzae. Throughout the surveillance in 2007, 2010, and 2012
8 62d 70a in Japan [25] and during our study, there were no signs of signifi-
cant change in the frequency of resistant strains of H. influenzae.
A significant increase in non-PCV13 serotypes was observed in
children with invasive pneumococcal diseases (IPD) (38/403, 9.4%
in 2008e2010 to 95/308, 30.8% in 2011e2013) in 10 prefectures in
Japan [16]. Recent dominant strains of S. pneumoniae in Japan in
invasive diseases were 19A, 24 or 24F, 15A, 15C, and 22F in children
in 2012e2014 [26,27], similar to our study that showed 15A, 15B/
15C, 24F, and 35B were dominant. In the US, the four most frequent
causes of IPD during 2011e2013 were serotypes 33F, 22F, 15B/15C,
and 35B after 13-valent conjugate vaccine implementation in 2010
[28]. Also, in England and Wales, non-PCV13 serotypes 24F, 15B/C,
22F, 33F, 15A, 23B, 8, and 12 became dominant in people under 5
years in 2012/2013 and 2013/2014. The incidence of non-PCV13
type invasive pneumococcal disease in children under 2 years
and 2e4 years, compared with the pre-PCV baseline, increased by
94 and 192% (incidence rate ratio of 1.94, 1.42e2.63, and 2.92,
1.76e4.82), respectively [29]. Although the dominant strains differ

Please cite this article in press as: Shinjoh M, et al., Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after the wide use of
Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines, J Infect Chemother (2017), http://dx.doi.org/10.1016/
j.jiac.2017.02.014
 M. Shinjoh et al. / J Infect Chemother xxx (2017) 1e12 7

Fig. 3. Compliance with the Japanese guidelines [14] in the treatment of meningitis, 2013e2015
*Empiric therapy for those with negative gram staining or without gram staining of the cerebrospinal fluid, according to the Japanese guidelines:
1. neonatal with underlying disease, carbapenem þ vancomycin
2. neonatal without underlying disease, ampicillin þ cefotaxime
3. 1 month with underlying disease, carbapenem þ vancomycin
4. 1 month without underlying disease, carbapenem þ 3rd generation cephalosporin ± vancomycin
**Definite treatment according to the Japanese guideline:
1. For H. influenza, ampicillin, cefotaxime, ceftriaxone, carbapenem, or cefotaxime þ meropenem
2. For S. pneumoniae, ampicillin, panipenem, cefotaxime, ceftriaxone, or panipenem þ vancomycin
3. For S. agalactiae, ampicillin or cefotaxime
4. For E. coli, cefotaxime, meropenem or panipenem

Fig. 4. The use of dexamethasone in bacterial meningitis in children, 2013e2015.

from country to country, the seroreplacement in IPD and increase in
non-PCV serotypes has become a major problem worldwide.
As strain 19A is included in PCV 13 but not in PCV 7, 19A is ex-
pected to be eliminated. Because most of the invasive strains
included in PCV such as 6A, 6B, 14, 19F, and 23F were penicillin
resistant [27], the overall penicillin susceptibility was seen to be
improving in our present study. However, the rate of penicillin
resistant strains may increase if the non-PCV strains 15A and 35B
increase, because most of these strains were penicillin resistant [27].
More than half of the empirical treatment for those with nega-
tive gram staining or without gram staining of the cerebrospinal
fluid was different from that outlined in the Japanese guidelines [14]
(Fig. 3). However, as shown in the Results, most cases used more
antimicrobials than were recommended in the guidelines.

Please cite this article in press as: Shinjoh M, et al., Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after the wide use of
Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines, J Infect Chemother (2017), http://dx.doi.org/10.1016/
j.jiac.2017.02.014
8 M. Shinjoh et al. / J Infect Chemother xxx (2017) 1e12

H. influenzae meningitis is decreasing and corticosteroids are pref-

erably used for H. influenzae and S. pneumoniae (Fig. 4), and the
overall prognosis is improving (Fig. 5).
Staphylococcus sp. as a newly analyzed risk factor, consciousness
disturbance, convulsion at onset, and low CSF glucose were associ-
ated with poor outcome in our study. The last two were also asso-
ciated with the outcome in our last report [10]. Recently reported
risk factors were similar to those in our report, such as seizure [31],
CSF glucose <20 mg/dl [31], symptom duration >3 days [31], coma
[31,32], impaired consciousness [32], and pneumococcal meningitis
[32]. Pneumococcal meningitis is not associated with poor outcome
in our observational studies [10] (Table 1). In our data base, the
empiric antimicrobials in six death cases with pneumococcal men-
ingitis since 2011 were recorded, and three of them used third
cephalosporin and meropenem, and two used third cephalosporin
and vancomycin. Although none of the death cases used panipenem,
which is the most widely used carbapenem for pneumococcal
Fig. 5. Case fatality rate of bacterial meningitis in children, 1979e2015.
meningitis only in Japan, whether a better outcome resulted from
using panipenem or not is still uncertain. Staphylococcal meningitis
Therefore, the prognosis was not significantly different between
is a new risk factor even after adjustment for the factors such as
those within and outside of the guidelines (Table 3). According to
hospital acquired, consciousness disturbance, convulsions, and low
the recent meta-analysis, the use of corticosteroid (usually dexa-
CSF glucose. We did not analyze Staphylococcal meningitis sepa-
methasone) is effective. Corticosteroids reduced severe and any
rately because the number was small. However, the fact that most of
hearing loss in children, severe hearing loss in children with
these cases had intracranial disease indicates some intracranial
H. influenzae meningitis, and mortality with S. pneumoniae, but did
factors may influence the prognosis.
not reduce overall mortality in children, severe hearing loss in
As shown in our previous report [10], there are some limitations
children with non-H. influenzae meningitis, or mortality with
to this study. We could not show the incidence per 100,000 from
H. influenzae [30]. We could not prove the effectiveness of cortico-
our study, as this was not a population-based study. A population-
steroids for children (Table 3), partly because the total and

Table 3
Risk factors for death or sequelaea (2013e2015).

Possible risk factors Outcome (prognosis) Univariate analysis Multivariate analysis

Good outcome Poor outcome total odds (95%CI) p odds (95%CI) p

N ¼ 294 N ¼ 93

without with without with

risk factors risk factors

Patients age<1M 219 75 64 29 387 1.323 (0.794e2.206) 0.283

status age<4M 136 158 43 50 387 1.001 (0.627e1.598) 0.997
age<12M 104 190 26 67 387 1.411 (0.845e2.354) 0.188
nursery school 261 19 76 8 364 1.446 (0.609e3.433) 0.403
female 157 134 57 35 383 0.719 (0.445e1.163) 0.179
hospital-acquiredb 217 55 55 28 355 2.009 (1.167e3.456) 0.012 1.980 (0.941e4.166) 0.072
intracranial underlying diseases 246 48 75 18 387 1.230 (0.675e2.242) 0.499
sinusitis 274 16 88 4 382 0.778 (0.254e2.390) 0.662
Symptoms consciousness disturbanceb 190 84 33 51 358 3.496 (2.104e5.807) 0.000 2.617 (1.323e5.176) 0.006
convulsionb 255 38 57 34 384 4.003 (2.322e6.900) 0.000 4.057 (1.987e8.283) 0.000
duration among those with 32 24 56 1.011 (0.992e1.032) 0.256
convulsion
Patients low CSF glucose <20b 192 93 32 55 372 3.548 (2.150e5.857) 0.000 2.892 (1.563e5.351) 0.001
data low CSF glucose <15 205 80 36 51 372 3.630 (2.205e5.978) 0.000
Microbiology H. influenzae 283 11 92 1 387 0.280 (0.036e2.195) 0.226
S. pneumoniae 221 73 70 23 387 0.995 (0.580e1.707) 0.985
S. agalactiae 193 101 62 31 387 0.955 (0.583e1.565) 0.856
E. coli 264 30 85 8 387 0.828 (0.366e1.875) 0.651
Staphylococcus sp.b 265 29 76 17 387 2.044 (1.066e3.918) 0.031 4.283 (1.774e10.340) 0.001
Treatment initial treatment (combination) 29 265 13 78 385 0.657 (0.326e1.324) 0.240
empiric therapy not accordance 25 38 8 8 79 0.658 (0.224e1.926) 0.455
with guidelinesc
positive CSF culture on the next 101 30 34 8 173 0.792 (0.331e1.893) 0.600
day
use of dexamethazone 168 123 52 40 383 1.051 (0.655e1.687) 0.838
for H. influenzae, 2011e2015 4 100 1 17 122 0.680 (0.072e6.457) 0.737
for S. pneumoniae, 2011 33 92 7 30 162 1.537 (0.616e3.834) 0.356
e2015
for S. agalactiae, 2011e2015 95 62 33 23 213 1.068 (0.574e1.987) 0.836
a
Transient lesions such as subdural effusion were excluded in “sequelae” (included in “good outcome”).
b
Multivariate analysis was performed.
c
For those without or negative gram staining of the cerebrospinal fluid at onset.

Please cite this article in press as: Shinjoh M, et al., Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after the wide use of
Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines, J Infect Chemother (2017), http://dx.doi.org/10.1016/
j.jiac.2017.02.014
 M. Shinjoh et al. / J Infect Chemother xxx (2017) 1e12 9

Table 4 Table 4 (continued )

The 366 cooperating institutes in Japan.
Chiba Kaihin Municipal Hospital
Hokkaido (North) (20) Japanese Red Cross Narita Hospital
Hokkaido University Hospital Asahi General Hospital
Sapporo Medical University Hospital Funabashi Municipal Medical Center
Asahikawa Medical University Hospital Toho University Sakura Medical Center
Nayoro City General Hospital Chiba Aoba Manicipal Hospital
Sapporo City General Hospital Teikyo University Chiba Medical Center
Hokkaido P.W.F.A.C Asahikawa-Kosei General Hospital Chiba Children's Hospital
Hokkaido P.W.F.A.C Sapporo-Kosei General Hospital Nippon Medical School Chiba Hokusoh Hospital
NTT East Sapporo Hospital Funabashi Futawa Hoapital
Hakodate Municipal Hospital Kameda Medical Center
Hakodate Central General Hospital Tokyo Women's Medical University Yachiyo Medical Center
Asahikawa City Hospital Chibanishi General Hospital
Teine Keijinkai Hospital Toukatsu Hospital
Tomakomai City Hospital Toho University Ohashi Medical Center
Sapporo Hokushin Hospital Nihon University Itabashi Hospital
Sapporo Tokushukai Hospital University Hospital of Medicine Tokyo Medical and Dental University
Hokkaido Medical Center for Child Health and Rehabilitation Toho University Omori Medical Center
Sapporo Hokuyu Hospital Keio University Hospital
Ebetsu City Hospital Tokyo Women's Medical University Medical Center East
Hokkaido P.W.F.A.C. Obihiro-Kosei General Hospital Nippon Medical School Hospital
Hokkaido P.W.F.A.C. Abashiri-Kosei General Hospital Kyorin University Hospital
Tohoku (North East) (24) The University of Tokyo Hospital
Hirosaki National Hospital Teikyo University Hospital
Aomori Prefectural Center Hospital Tokyo Medical University Hospital
Aomori City Hospital Nippon Medical School Tama Nagayama Hospital
Iwate Medical University Hospital Tokyo Metropolitan Bokutoh Hospital
Akita University Hospital Fussa Hospital
Japanese Red Cross Akita Hospital St. Luke's International Hospital
Akita Kousei Medical Center The Frateruity Memorial Hospital
Hiraka General Hospital Musashino Red Cross Hospital
Odate Municipal General Hospital Tachikawa Sougo General Hospital
Yamagata University Hospital Japanese Red Cross Medical Center
Yamagata City Hospital SAISEIKAN Tachikawa Kyosai Hospital
Yamagata Prefectural Central Hospital Tokyo Teishin Hospital
Tsuruoka Municipal Shonai Hospital Tokyo Metropolitan Ohtsuka Hospital
Tohoku University Hospital Tokyo Metropolitan Health and Medical Treatment Corporation Toshima
Sendai Medical Center Hospital
Sendai City Hospital Showa University School of Medicine
Saka General Hospital National Center for Child Health and Development
Japanese Red Cross Sendai Hospital Tokyo Rinkai Hospital
South Miyagi Medical Center National Hospital Organization Tokyo Medical Center
Fukushima Medical University National Cancer Center Hospital
Takeda General Hospital Tokyo-Kita Medical Center
Iwaki Kyoritsu General Hospital Showa General Hospital
Jusendo General Hospital Yuasa Foundation Juntendo University Nerima Hospital
Ohara General Hospital Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital
Kanto (East, Capital region) (105) Hino Municipal Hospital
University of Tsukuba Hospital Tokai University Hachioji Hospital
Hitachi General Hospital Tokyo Metropolitan Kita Medical and Rehabilitation Center
Tsukuba Gakuen Hospital Tokyo Metropolitan Children's Medical Center
Tsukuba Medical Center Hospital Tokyo Metropolitan Health and Medical Treatment Corporation Tama-Hokubu
Hitachi, Ltd. Hitachinaka General Hospital Medical Center
JA Toride General Medical Center Musashimurayama Hospital
Ibaraki Seinan Medical Center Hospital National hospital Organization Disaster Medical Center
Jichi Children's Medical Center Tochigi Teikyo University School of medicine University Hospital, Mizonokuchi
Haga Red Cross Hospital St. Marianna University School of Medical Hospital
Gunma University Hospital Tokai University School of Medicine
Isesaki Municipal Hospital Showa University Fujigaoka Hospital
Kiryu Kosei General Hospital Sagamihara National Hospital
Fuji Heavy Industries Health Insurance Society Ota Memorial Hospital Kanagawa Children's Medical Center
Gunma Chuo General Hospital Yokohama Municipal Citizen's Hospital
National Hospital Organization Takasaki General Medical Center Odawara Municipal Hospital
Saitama Medical University Hospital Yokohama Minami Kyousai Hospital
National Defense Medical College Hiratsuka Kyosai Hospital
Saitama Medical School Saitama Medical Center Saiseikai Yokohamashi Nanbu Hospital
Dokkyo Medical University Koshigaya Hospital Yokosuka Kyosai Hospital
Nishisaitama-chuo National Hospital Kawasaki Kyodo hospital
Toda Central General Hospital Nippon Medical School Musasi Kosugi Hospital
Saiseikai Kawaguchi General Hospital Sagamihara Kyodo Hospital
Koshigaya Municipal Hospital Yokohama City Minato Red Cross Hospital
Saitama cooperative hospital Ebina General Hospital
Jichi Medical University Saitama Medical Center St. Marianna University School of Medicine, Yokohama City Seibu Hospital
National Hospital Organization Saitama National Hospital National Hospital Organization Yokohama Medical Center
Juntendo University Urayasu Hospital Yokohama City University Medical Hospital
Chiba University Hospital Yokohama Rosai Hospital
National Hospital Organization Shimoshizu National Hospital Saiseikai Yokohamashi Tobu Hospital
(continued on next page)

Please cite this article in press as: Shinjoh M, et al., Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after the wide use of
Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines, J Infect Chemother (2017), http://dx.doi.org/10.1016/
j.jiac.2017.02.014
10 M. Shinjoh et al. / J Infect Chemother xxx (2017) 1e12

Table 4 (continued ) Table 4 (continued )

National Hospital Organization Kanagawa Hospital Naga Municipal Hospital

Chubu (Middle East) (61) Wakayama Medical University
Niigata University Medical and Dental Hospital Japanese Red Cross Wakayama Medical Center
Niigata Prefectural Shibata Hospital Nara Municipal Hospital
Saiseikai Niigata Daini Hospital Kyoto University Hospital
Hamamatsu University Hopital Kyoto Katsura Hospital
Shizuoka City Shimizu Hospital National Hospital Organization Maizuru Medical Center
Fuji City General Hospital The Japan Baptist Hospital
Shizuoka Saiseikai General Hospital Rakuwakai Otowa Hospital
Seirei Hamamatsu General Hospital Nantan General Hospital
Japanese Red Cross Shizuoka Hospital Kyoto Kuramaguchi Medical Center
Hamamatsu Medical Center Kinki University Hospital
Numazu city Hospital Osaka Medical College Hospital
Juntendo University Shizuoka Hospital Osaka City University Hospital
IUHW Atami Hospital Osaka Prefectural Medical Center for Respiratory and Allegic Diseases
Iwata City Hospital Osaka General Medical Center
Yaizu City Hospital Sakai City Medical Center
Fujinomiya City General Hospital Toyonaka Municipal Hospital
University of Yamanashi Hospital Minoh City Hospital
Kofu-Kyoritsu hospital Izumi Municipal Hospital
Shinshu University Hospital JCHO Osaka Hospital
Saku Central Hospital Osaka Rosai Hospital
Iida Municipal Hospital Takatsuki General Hospital
Gifu University Hospital PL Hospital
Gifu Prefectural General Medical Center Osaka Police Hospital
Kizawa Memorial Hospital Bellland General Hospital
Japanese Red Cross Takayama Hospital Hannan Chuo Hospital
Gifu Municipal Hospital Suita Municipal Hospital
University of Toyama Hospital Yodogawa Christian Hospital
Toyama Prefectural Central Hospital Kitano Hospital, The Tazuke Kofukai Medical Research Institute
Kouseiren Takaoka Hospital Osaka Medical Center and Research Institute for Maternal and Child Health
Toyama City Hospital Hoshigaoka Medical Center
Kanazawa University Hospital Osaka City Juso Hospital
Kanazawa Medical University Hospital Osaka City Sumiyoshi Hospital
National hospital Organization Iou Hospital Ikeda City Hospital
Ishikawa Prefectural Central Hospital Saiseikai Nakatsu Hospital
University of Fukui Hospital Saiseikai Suita Hospital
Japanese Red Cross Fukui Hospital Higashiosaka City General Hospital
Fukui Prefectural Hospital Osaka City General Hospital
Nagoya University Hospital Kawachi General Hospital
Aichi Medical University Hospital Yao Municipal Hospital
Komaki City Hospital Hirakata City Hospital
Chubu Rosai Hospital Komatsu Hospital
Anjo Kosei Hospital Kishiwada Tokushukai Hospital
Okazaki City Hospital Matsushita Memorial Hospital
Japanese Red Cross Nagoya Daini Hospital National Hospital Organization Osaka Minami Medical Center
JCHO Chukyo Hospital Aizenbashi Hospital
Hekinan Municipal Hospital Kansai Medical University Takii Hospital
Toyokawa City Hospital National Cerebral and Cardiovascular Center
Tosei General Hospital Chibune General Hospital
Gamagori City Hospital Kashiwara Municipal Hospital
Toyota Kosei Hospital Rinku General Medical Center
Minami Seikyo Hospital National Hospital Organization Osaka National Hospital
Kainan Hospital Kobe University Hospital
Daido Hospital Hyogo College of medicine
Banbuntane Hotokukai Hospital Kobe City Medical Center General Hospital
Nagoya City University Hospital Itami City Hospital
Nagoya Medical Center Kakogawa East City Hospital
Konan Kosei Hospital JCHO Kobe Central Hospital
Handa City Hospital Nishi Kobe Medical Center
Meitetsu Hospital Toyooka Public Hospitals' Association Toyooka Hospital
Daiyukai General Hospital kakogawa West City Hospital
Aichi Prefectural Colony Central Hospital Saiseikai Hyogoken Hospital
Kansai (Middle West) (84) Rokko Island Kohnan Hospital
Ise Red Cross Hospital Kita Harima Medical Center
Yokkaichi Municipal Hospital Hyogo Prefectural Awaji Medical Center
NHO Mie Chuo Medical Center Akashi City Hospital
National Mie Hospital Nishinomiya Municipal Central Hospital
Suzuka General Hospital Himeji St. Mary's Hospital
Otsu Municipal Hospital Kobe City Medical Center West Hospital
Shiga Medical Center for Children Chugoku (West) (18)
Omihachiman Community Medical Center Kawasaki Medical School Hospital
Nagahama City Hospital Japanese Red Cross Okayama Hospital
Nagahama Red Cross Hospital Shigei Medical Research Hospital
Nara Medical University Hospital Kurashiki Medical Center
Nara Prefecture General Medical Center Hiroshima Prefectural Hospital
Nara Prefectural Seiwa Medical Center Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital
Yamato Takada Municipal Hospital Hiroshima City Asa Hospital

Please cite this article in press as: Shinjoh M, et al., Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after the wide use of
Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines, J Infect Chemother (2017), http://dx.doi.org/10.1016/
j.jiac.2017.02.014
 M. Shinjoh et al. / J Infect Chemother xxx (2017) 1e12 11

Table 4 (continued ) H. influenzae and S. pneumoniae. Seroreplacement for pneumo-

JA Onomichi General Hospital coccus was observed to be similar to that seen in other countries.
National Hospital Organization Kure Medical Center Since the advent of these vaccines, S. agalactiae has become the
JA Hiroshima General Hospital most common organism involved in bacterial meningitis in Japan.
Yamaguchi University Hospital Therefore it will be necessary to monitor and focus on the invasive
Shimonoseki City Hospital
Tokuyama Central Hospital
diseases due to S. agalactiae including b-lactam or macrolide sus-
Tottori University Hospital ceptibility of isolates [33], late-onset diseases [34] and GBS
Tottori Prefectural Central Hospital vaccines.
Shimane University Hospital
Shimane Prefectural Central Hospital
Matsue Red Cross Hospital Conflict of interest
Shikoku (Middle West Island) (16)
Shikoku Medical Center for Children and Adults On behalf of all authors, the corresponding author states that
Kagawa prefecture Central Hospital
there is no conflict of interest related to the study.
Takamatsu Red Cross Hospital
Yashima General Hospital
Mitoyo General Hospital Acknowledgements
Tokushima University Hospital
Tokushima Prefectural Central Hospital
Tokushima Red Cross Hospital
We thank all the medical doctors from the 366 institutes
Kochi Medical School Hospital (Table 4) who returned the questionnaire. We would also like to
Kochi Health Sciences Center express our gratitude to Ms. Ikuko Iwata and Ms. Sayuri Kayama for
Kochi National Hospital her administrative support. We dedicate this work to the deceased
Japanese Red Cross Kochi Hospital
Dr Keisuke Sunakawa who planned and organized the study.
Ehime University Hospital
Uwajima City Hospital
Ehime Prefectural Imabari Hospital References
Ehime Prefectural Niihama Hospital
Kyushu and Okinawa (West and South) (38) [1] Kobayashi Y, Haruta T, Morikawa Y, Fujiwara T. Trend of bacterial meningitis
Hospital of the University of Occupational and Environmental Health in children over a 13-year period (1966 through 1978) in Japan. An analysis
Kyushu University Hospital based on studies in 127 institutions (author's transl). Jpn J Antibiot 1979;32:
Kurume University Hospital 795e805 [In Japanese].
Fukuoka University Hospital [2] Fujii R, Hiraiwa M, Nonaka C, Kobayashi Y. Trends in childhood bacterial
JCHO Kyushu Hospital meningitis in Japan (1979-1984). (Part 1). On the causative organisms. Kan-
Iizuka Hospital senshogaku zasshi J Jpn Assoc Infect Dis 1986;60:592e601 (In Japanese).
National Hospital Organization Fukuoka Hospital [3] Iwata S. Penicillin-resistant Streptococcus pneumoniae. J Pediatr Infect Dis
Kitakyushu Municipal Medical Center Immunol 1998;10:139e46 (In Japanese).
[4] Sunakawa K, Nonoyama M, Takayama Y, Yamaguchi Y, Ooishi T, Iwata S, et al.
Fukuoka University Chikushi Hospitall
The trend of childhood bacterial meningitis in Japan (1997.7-2000.6). Kan-
National Hospital Organization Kokura Medical Center
senshogaku zasshi J Jpn Assoc Infect Dis 2001;75:931e9 (In Japansese).
Fukuoka Tokushukai Hospital
[5] Sunakawa K, Nonoyama M, Ooishi T, Iwata S, Akita H, Sato Y, et al. The trend of
National Hospital Organization Kyushu Medical Center childhood bacterial meningitis in Japan (2000-2002). Kansenshogaku zasshi J
National Hospital Organization Fukuoka-higashi Medical Center Jpn Assoc Infect Dis 2004;78:879e90 (In Japansese).
Kitakyushu General Hospital [6] Sunakawa K, Nonoyama M, Ooishi T, Iwata S, Akita H, Sato Y, et al. Trends in
Takagi Hospital pediatric bacterial meningitis in Japan (2003-2004). Kansenshogaku zasshi J
Fukuoka Shin Mizumaki Hospital Jpn Assoc Infect Dis 2006;80:27e38 (In Japansese).
Oita Prefectural Hospital [7] Sunakawa K, Ubukata K, Chiba N, Hasegawa K, Nonoyama M, Iwata S, et al.
Nakatsu Municipal Hospital Childhood bacterial meningitis trends in Japan from 2005 to 2006. Kansen-
National Hospital Organization Beppu Medical Center shogaku zasshi J Jpn Assoc Infect Dis 2008;82:187e97 (In Japansese).
Almeida Memorial Hospital [8] Sunakawa K, Sakai F, Hirao Y, Hanaki H, Nonoyama M, Iwata S, et al. Childhood
Saga University Hospital bacterial meningitis trends in Japan from 2007 to 2008. Kansenshogaku zasshi
National Hospital Organization Ureshino Medical Center J Jpn Assoc Infect Dis 2010;84:33e41 (In Japansese).
[9] Shinjoh M, Iwata S, Sato Y, Akita H, Sunakawa K. Childhood bacterial men-
Saga-Ken Medical Center Koseikan
ingitis trends in Japan from 2009 to 2010. Kansenshogaku zasshi J Jpn Assoc
Nagasaki University Hospital
Infect Dis 2012;86:582e91 (In Japanese).
Sasebo City General Hospital [10] Shinjoh M, Iwata S, Yagihashi T, Sato Y, Akita H, Takahashi T, et al. Recent
National Hospital Organization Nagasaki Medical Center trends in pediatric bacterial meningitis in Japanea country where Haemo-
Kumamoto City Hospital philus influenzae type b and Streptococcus pneumoniae conjugated vaccines
Japanese Red Cross Kumamoto Hospital have just been introduced. J Infect Chemother 2014;20:477e83.
National Hospital Organization Kumamoto Medical Center [11] http://www.nih.go.jp/niid/ja/bac-megingitis-m/bac-megingitis-iasrtpc/4176-
Kumamoto Chuo Hospital tpc406-j.html. (Accessed 27 December 2016).
University of Miyazaki Hospital [12] Nakayama T. Vaccine chronicle in Japan. J Infect Chemother 2013;19:787e98.
Miyazaki Prefectural Miyazaki Hospital [13] http://www.e-stat.go.jp/SG1/estat/eStatTopPortalE.do. (Accessed 27
Kagoshima University Medical and Dental Hospital December 2016).
Kagoshima Seikyo Hospital [14] Societas Neurologica Japonica JSoNT. Japanese society for neuroinfectious
Ryukyu University Hospital diseases. Pract Guidel Bact Meningitis 2014;2014.
[15] http://www.mhlw.go.jp/toukei/saikin/hw/hoken/national/22.html. (Accessed
Okinawa Prefectural Chubu Hospital
27 December 2016).
Nakagami Hospital
[16] Suga S, Chang B, Asada K, Akeda H, Nishi J, Okada K, et al. Nationwide
Okinawa Prefectural Nanbu Medical Center, Children's Medical Center
population-based surveillance of invasive pneumococcal disease in Japanese
children: effects of the seven-valent pneumococcal conjugate vaccine. Vaccine
2015;33:6054e60.
based study is difficult, especially in urban areas because the pa- [17] http://www.nih.go.jp/niid/ja/allarticles/surveillance/2300-iasr/related-arti-
cles/related-articles-416/5025-dj4163.html. (Accessed 27 December 2016).
tients are admitted to various hospitals, and not always to partic-
[18] http://www.stat.go.jp/data/jinsui/2.htm. (Accessed 27 December 2016).
ular medical centers. However, the decrease in the rate of incidence [19] http://www.mhlw.go.jp/toukei/list/dl/130-28_1.pdf. (Accessed 4 January 2017).
per total admissions in these 3 years was similar to the reported [20] http://www.e-stat.go.jp/SG1/estat/GL08020103.do?_toGL08020103_&listID¼
rate per population [16]. 000001141596&. (Accessed 4 January 2017).
[21] Schuchat A, Robinson K, Wenger JD, Harrison LH, Farley M, Reingold AL, et al.
In conclusion, Hib vaccine and PCV decreased the total number Bacterial meningitis in the United States in 1995. Active surveillance team.
of cases with pediatric bacterial meningitis in Japan caused by N. Engl J Med 1997;337:970e6.

Please cite this article in press as: Shinjoh M, et al., Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after the wide use of
Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines, J Infect Chemother (2017), http://dx.doi.org/10.1016/
j.jiac.2017.02.014
12 M. Shinjoh et al. / J Infect Chemother xxx (2017) 1e12

[22] Hsu HE, Shutt KA, Moore MR, Beall BW, Bennett NM, Craig AS, et al. Effect of
pneumococcal conjugate vaccine on pneumococcal meningitis. N. Engl J Med
2009;360:244e56.
[23] http://www.nih.go.jp/niid/ja/id/738-disease-based/sa/bac-megingitis/idsc/ia
sr-news/5864-pr4271.html. (Accessed 27 December 2016).
[24] Hoshino T, Hachisu Y, Kikuchi T, Tokutake S, Okui H, Kutsuna S, et al. Analysis
of Haemophilus influenzae serotype f isolated from three Japanese children
with invasive H. influenzae infection. J Med Microbiol 2015;64:355e8.
[25] Baba H, Sato Y, Toyonaga Y, Hanaki H, Sunakawa K. Nationwide survey of the
development of drug resistance in the pediatric field in 2007, 2010, and 2012:
drug sensitivity of Haemophilus influenzae serotype b strain in Japan. J Infect
Chemother 2015;21:277e83.
[26] Nakano S, Fujisawa T, Ito Y, Chang B, Suga S, Noguchi T, et al. Serotypes,
antimicrobial susceptibility, and molecular epidemiology of invasive and non-
invasive Streptococcus pneumoniae isolates in paediatric patients after the
introduction of 13-valent conjugate vaccine in a nationwide surveillance
study conducted in Japan in 2012-2014. Vaccine 2016;34:67e76.
[27] Chiba N, Morozumi M, Shouji M, Wajima T, Iwata S, Ubukata K, et al. Changes
in capsule and drug resistance of Pneumococci after introduction of PCV7,
Japan, 2010-2013. Emerg Infect Dis 2014;20:1132e9.
[28] Metcalf BJ, Gertz Jr RE, Gladstone RA, Walker H, Sherwood LK, Jackson D, et al.
Strain features and distributions in pneumococci from children with invasive
disease before and after 13-valent conjugate vaccine implementation in the
USA. Clin Microbiol Infect 2016;22. 60 e9ee29.
[29] Waight PA, Andrews NJ, Ladhani SN, Sheppard CL, Slack MPE, Miller E. Effect
of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal
disease in England and Wales 4 years after its introduction: an observational
cohort study. Lancet Infect Dis 2015;15:535e43.
[30] Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute
bacterial meningitis. Cochrane Database Syst Rev 2015:CD004405.
[31] Olson D, Lamb MM, Gaensbauer JT, Todd JK, Halsey NA, Asturias EJ, et al. Risk
factors for death and major morbidity in Guatemalan children with acute
bacterial meningitis. Pediatr Infect Dis J 2015;34:724e8.
[32] McCormick DW, Wilson ML, Mankhambo L, Phiri A, Chimalizeni Y, Kawaza K,
et al. Risk factors for death and severe sequelae in Malawian children with
bacterial meningitis, 1997-2010. Pediatr Infect Dis J 2013;32:e54e61.
[33] Morozumi M, Wajima T, Kuwata Y, Chiba N, Sunaoshi K, Sugita K, et al. As-
sociations between capsular serotype, multilocus sequence type, and mac-
rolide resistance in Streptococcus agalactiae isolates from Japanese infants
with invasive infections. Epidemiol Infect 2014;142:812e9.
[34] Hosoda A, Gatayama R, Moriyama S, Ishii N, Yamada K, Matsuzaki Y, et al. The
first case of recurrent ultra late onset group B streptococcal sepsis in a 3-year-
old child. IDCases 2017;7:16e8.

Please cite this article in press as: Shinjoh M, et al., Pediatric bacterial meningitis in Japan, 2013e2015 e 3e5 years after the wide use of
Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines, J Infect Chemother (2017), http://dx.doi.org/10.1016/
j.jiac.2017.02.014