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Original Article
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.
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 pediatric centers in Japan (15/26). The results revealed 407 (139,
regional governments in November 2010 and were then covered as 124 and 139 for 2013, 2014 and 2015, and 5 for unknown year
routine recommended vaccines in April 2013 [12]. In November between 2013 and 2015) patients with pediatric meningitis were
2013, PCV 13 (Prevenar 13®, Pfeizer Japan Inc.) replaced PCV 7. The reported at 165 hospitals. The remaining 201 hospitals experienced
incidence of bacterial meningitis due to these organisms showed a no meningitis cases. The new pediatric admissions at 366 hospitals
decrease in 2011 and 2012, but meningitis due to S. agalactiae and were approximately 360,000 each year (Table 1). Patients included
E. coli remained unchanged. The purpose of this study is to provide 225 males and 178 females, and for 4 patients, the gender was not
an overview of recent trends in bacterial meningitis and the impact reported. The age distribution is shown in Fig. 1. The patients'
of immunization with Hib vaccine and PCV in Japan. Here, we median age was 3 months. There were 3.9% of patients (16/407)
present the surveillance questionnaire data, including the newly who were immunocompromised. Underlying intracranial diseases
obtained data from 2013 to 2015. 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/
2. Patients and methods 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,
A cross-sectional, multicenter, non-interventional study was S. agalactiae, E. coli, S. aureus, coagulase-negative Staphylococcus,
conducted in Japan in December 2015. Similar methods were used and others, respectively.
as reported [10]. Questionnaires were sent to the same 517 hospi- The causative organisms in 2013e2015 and the trends since
tals as in the 2011e2012 survey, including almost all university 1966 are shown in Fig. 2a and b, respectively. S. agalactiae (33%)
hospitals, pediatric centers, and public hospitals with pediatric were the most observed organisms, followed by S. pneumoniae
admissions from all districts in Japan. The questionnaires included (25%) and E. coli (10%). H. influenzae had been the most common
questions on pediatric and neonatal bacterial meningitis reported between 1976 and 2011, but S. agalactiae took over that position.
at each institute in 2013e2015. Bacterial meningitis was defined as The incidence rate per 1000 admissions (407 cases in 366 hos-
a systemic infection with positive bacterial culture or PCR in the pitals) is shown in Table 1. The case rates for total and H. influenzae
CSF, or pleocytosis in CSF with positive blood bacterial culture. The meningitis were significantly lower in 2013e2015 compared to in
annual number of new pediatric admissions at each institution was 2009e2010 (1.20 to 0.38 and 0.66 to 0.01, p < 0.001), and 2011e2012
recorded. The amount of Hib and PCV vaccines that were produced (0.55 to 0.38 and 0.19 to 0.01, p < 0.001), respectively. The rates for
(data from the Japanese Association of Vaccine Industries, Tokyo, S. pneumoniae was also lower in 2013e2015 compared to in
Japan), and the portal site of official statistics of Japan, “e-Stat” [13] 2009e2010 (0.30 to 0.09, p < 0.001), but not in 2011e2012 (0.11 to
were used to estimate the coverage rate. We also used the database 0.09, p ¼ 0.22). The rate for S. agalactiae and E. coli remained un-
that included information from previous, similar surveys that were changed in 2013e2015 compared to in 2009e2010 (0.10 to 0.13 and
performed [1e10]. 0.04 to 0.04, p ¼ 0.19 and p ¼ 0.82) and 2011e2012 (0.13 to 0.13 and
We reported the epidemiological data of pediatric bacterial 0.04 to 0.04, p ¼ 0.90 and p ¼ 0.83), respectively. Only 0e2 cases with
meningitis including the information on age, causative organisms, N. meningitidis were reported each year throughout 2001e2015.
antimicrobial resistance, used antibiotics, dexamethasone use,
compliance with Japanese guidelines, and prognosis. We also 3.2. H. influenzae and S. pneumoniae serotypes
calculated the case rates per 1000 pediatric admissions (total
number of meningitis patients/all pediatric admissions 1000) Of the 12 patients with H. influenzae, 11 were serotyped and 6 of
instead of using a population-based method. All data were the patients (55%) were confirmed as having the type b serotype
collected from all areas of Japan, and the sample size was similar to meningitis. Of these, only one patient (17%) had been vaccinated
that of the survey of 2011e2012 [10] (Table 1). (twice) but had no sequelae. One of the five unvaccinated Hib pa-
Statistical analysis was performed by using SPSS 22.0 software tients, who did not receive dexamethasone, had mild hearing loss.
(IBM, US) or Ekuseru-Toukei 2015 for Windows software program Among five patients with non-Hib, two were non-typeable, and
(Social Survey Research Information Co., Ltd., Tokyo, Japan). three were unknown. All five had no sequelae.
P < 0.05 was considered statistically significant for all analyses, Of the 101 patients with S. pneumoniae, 70 had information on
including the risk factor analysis. To analyze the risk factors, binary both serotypes and vaccine status (Table 2). Three patients were
logistic methods were chosen. First we did a univariate analysis, immunized and five unimmunized out of eight patients with PCV
and the risk factors from the univariate analysis (P < 0.1) were put serotypes, while 50 patients were immunized and 12 unimmunized
in a multivariate analysis by the forced entry method. Dependent out of 62 patients with non-PCV serotypes. Pneumococcal infection
valuables considered in the models were “poor outcome” related to PCV serotypes tended to be observed among PCV-
(including death, hearing loss, epilepsy, mental retardation, or unvaccinated children (p ¼ 0.017). Serotype 15A (11 cases [18%]),
bedridden) but transient lesions such as subdural fluid collection 15B or C (9 [15%]), 24F (8 [13%]), and 35B (7 [11%]) were the most
were included in “good outcome,” and the covariates (independent observed among 62 cases with non-PCV serotypes. Two cases with
valuables) were the same as previously reported items [10], “hos- serotype 19A were observed in July 2013 (immunized with PCV 7
pital-acquired” and “Staphylococcus sp. (including Staphylococcus only), and February 2014 (non-immunized).
aureus)” as a causative organism.
The study was approved by the Keio University Ethics Com- 3.3. Penicillin susceptibility of H. influenzae and S. pneumoniae
mittee (No. 2011029). (Table 1)
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
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
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)
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)
(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
(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
20
38
46
16
3
(2.1)
(6.1)
(5.6)
(0.0)
172
34
15
95
33
36
6
8
0
(15/30).
Of 169 patients who used dexamethasone, 163 patients had
(29.4)
(1.1)
(1.2)
(0.0)
(4.2)
(0.0)
273
165
34
10
74
24
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
(10.5)
(1.9)
(1.5)
(0.0)
(0.0)
208
135
17
48
19
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
(3.1)
(1.5)
(7.9)
(7.7)
(0.0)
196
136
13
38
13
9
0
Patient fatality rate among cases with known outcome
(33.3)
2002
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
Table 3).
Table 1 (continued )
S. pneumoniae
S. agalactiae
4. Discussion
(rate %)
(rate %)
(rate %)
(rate %)
(rate %)
deaths
deaths
deaths
deaths
deaths
E. coli
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
in 2009e2010 [9], the reported cases were estimated to be 10% of The decreasing rate of bacterial meningitis due to H. influenzae,
all cases with bacterial meningitis in Japan using the portal site of S. pneumonia, and S. agalactiae is similar to the report of meningitis
the official statistics of Japan (e-stat [13]) and the official data of the in 10 prefectures [16,17]. They reported that the rate was 98%, 61%,
Ministry of Health, Labour and Welfare [15]. For the last study in and 28% for H. influenzae, S. pneumonia, and S. agalactiae, respec-
2011e2012 and the present study in 2013e2015, the number of tively between 2008 and 2010 and 2013. Our data showed the rate of
pediatric admissions increased threefold from the 2009e2010 decrease rate was 98% (0.68e0.02), 70% (0.28e0.08), and 8%
survey. Second, we reported the cases with meningitis due to (0.12e0.12) for H. influenzae, S. pneumonia, and S. agalactiae,
H. influenzae and S. pneumoniae at a rate approximately 1.5 times respectively, between 2009 and 2013 (Table 1). In the United States,
higher than Suga et al. [16,17] reported in 10 prefectures in 2013 where the Hib vaccine was introduced in 1987, the incidence of
(23% population of <5 years old, 1,181,000/5,239,000 [18]) (3 and 23 meningitis due to H. influenzae declined by 94% from 1986 to 1995
cases [Table 1] vs 2 and 13 cases [16,17] for children under 5 years (2.9e0.2 cases per 100,000 population) [21]. Also in the United
old, respectively). Third, the number of inpatients per day for 0e14 States, where PCV 7 was introduced in 2000, the overall incidence of
years in Japan in 2014 was 28,100 (¼10,256,500 per year) [19], and pneumococcal meningitis in children <2 years old declined by 64.0%
new admissions were estimated to be 1/10 (1,025,650), because the from 1998e1999 to 2004e2005 [22]. The relative difference in
average length of hospital stay was approximately 10 days for this incidence is quite similar, although Japan is 20 years and 10 years
age group [20]. New pediatric admissions in our study in 2014 behind in terms of the introduction of Hib and pneumococcal vac-
(350,842, [Table 1]) represented around 35% of this value. However, cines, respectively. Invasive meningococcal meningitis is rare in all
we estimated that more than 30e40% of cases were reported, as age groups in Japan even after the introduction of Hib vaccine and
60% of the university hospitals and pediatric centers returned the PCV in the present study. Also, the meningococcal vaccine is not
questionnaire, institutions where more cases with meningitis routinely used, as only 24 litters (48,000 doses) were distributed in
would typically be admitted. 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
Table 2 the Hif strains isolated in Japan in their study were classified as
S. pneumoniae and serotypinga (2013e2015). 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
Vaccinated with PCV 3b 50 53
necessary to monitor the possibility of seroreplacement with non-b
Unvaccinated with PCV 5c 12 17 H. influenzae. Throughout the surveillance in 2007, 2010, and 2012
total 8 62d 70a in Japan [25] and during our study, there were no signs of signifi-
a
Of 101 patients with S. pneumoniae, 73 had information on serotypes, and 70 cant change in the frequency of resistant strains of H. influenzae.
had information on both serotypes and vaccine status. A significant increase in non-PCV13 serotypes was observed in
b
Serotypes 3, 19A (immunized with PCV 7 only) and 19F. children with invasive pneumococcal diseases (IPD) (38/403, 9.4%
c
Serotypes 6A, 6B, 7F, 19A and 19F.
d
in 2008e2010 to 95/308, 30.8% in 2011e2013) in 10 prefectures in
Serotypes 15A (11 cases, 18%), 15B or C (9, 15%), 24F (8, 13%) and 35B (7, 11%)
were most observed.
Japan [16]. Recent dominant strains of S. pneumoniae in Japan in
invasive diseases were 19A, 24 or 24F, 15A, 15C, and 22F in children
Tokyo, Japan). A national surveillance system also reported only in 2012e2014 [26,27], similar to our study that showed 15A, 15B/
seven children (two children <5 years and five between 10 and 19) 15C, 24F, and 35B were dominant. In the US, the four most frequent
suffered from invasive meningococcal disease between April 2013 causes of IPD during 2011e2013 were serotypes 33F, 22F, 15B/15C,
and December 2014, although it is one of the diseases requiring and 35B after 13-valent conjugate vaccine implementation in 2010
reporting in Japan [23]. [28]. Also, in England and Wales, non-PCV13 serotypes 24F, 15B/C,
Serotype replacement and change in susceptibility of 22F, 33F, 15A, 23B, 8, and 12 became dominant in people under 5
H. influenzae and S. pneumoniae is a great concern of pediatricians. years in 2012/2013 and 2013/2014. The incidence of non-PCV13
Hoshino et al. [24] reported that a shift from Hib to non-typeable type invasive pneumococcal disease in children under 2 years
H. influenzae and encapsulated strains other than Hib (non-b), and 2e4 years, compared with the pre-PCV baseline, increased by
particularly serotypes a, e, and f (Hif), has been observed after the 94 and 192% (incidence rate ratio of 1.94, 1.42e2.63, and 2.92,
introduction of the Hib vaccine in other countries, and all three of 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
from country to country, the seroreplacement in IPD and increase in resistant strains may increase if the non-PCV strains 15A and 35B
non-PCV serotypes has become a major problem worldwide. increase, because most of these strains were penicillin resistant [27].
As strain 19A is included in PCV 13 but not in PCV 7, 19A is ex- More than half of the empirical treatment for those with nega-
pected to be eliminated. Because most of the invasive strains tive gram staining or without gram staining of the cerebrospinal
included in PCV such as 6A, 6B, 14, 19F, and 23F were penicillin fluid was different from that outlined in the Japanese guidelines [14]
resistant [27], the overall penicillin susceptibility was seen to be (Fig. 3). However, as shown in the Results, most cases used more
improving in our present study. However, the rate of penicillin 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
Table 3
Risk factors for death or sequelaea (2013e2015).
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
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
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
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
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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