Nationwide Surveillance of Macrolide-Resistant Mycoplasma

pneumoniae Infection in Pediatric Patients

Yasuhiro Kawai,a Naoyuki Miyashita,b Mika Kubo,a Hiroto Akaike,a Atsushi Kato,a Yoko Nishizawa,a Aki Saito,a Eisuke Kondo,a
Hideto Teranishi,a Tokio Wakabayashi,a Satoko Ogita,a Takaaki Tanaka,a Kozo Kawasaki,a Takashi Nakano,a Kihei Terada,a
Kazunobu Ouchia
Department of Pediatricsa and Department of Internal Medicine 1,b Kawasaki Medical School, Okayama, Japan

We conducted nationwide surveillance to investigate regional differences in macrolide-resistant (MR) Mycoplasma pneumoniae
strains in Japan. The prevalence of MR M. pneumoniae in pediatric patients gradually increased between 2008 and 2012. Although re-
gional differences were observed, high levels of MR genes were detected in all seven surveillance areas throughout Japan and ranged in
prevalence from 50% to 93%. These regional differences were closely related to the previous administration of macrolides.

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M ycoplasma pneumoniae is a common causative pathogen of
respiratory tract infections (RTIs) in children. During 2010
and 2012, epidemics of M. pneumoniae infection, especially
among children, occurred throughout Japan, and the incidences
were the highest that had been observed in the previous decade
(1). Macrolides are generally considered to be the first-choice
agents for the treatment of M. pneumoniae infection. In 2000,
however, M. pneumoniae strains showing resistance to macrolides
were isolated from clinical samples obtained from Japanese pedi-
atric patients with pneumonia, and macrolide resistance has be-
come widespread in Japan and China (2–7). Macrolide-resistant
(MR) M. pneumoniae is also emerging in pediatric populations in
other countries (8–13). However, data on MR M. pneumoniae
have mostly been reported for limited areas (2–5), and there are
no reports on regional differences in the prevalence of MR M.
pneumoniae throughout Japan. The purpose of our study was to
investigate regional differences in the prevalences, resistance
mechanisms, and drug susceptibilities of MR M. pneumoniae
strains by means of the first nationwide surveillance of MR M.
pneumoniae in Japan.
All pediatric patients with RTIs who visited 65 institutions located
in seven areas of Japan (A, Kyushu [13 million people]; B, Chugoku
[7 million people]; C, Shikoku [3 million people]; D, Kinki [20 mil-
lion people]; E, Tokai [15 million people]; F, Kanto [42 million peo- FIG 1 Samples were collected from pediatric patients with acute respiratory
ple]; and G, Hokkaido [5 million people]; Fig. 1) participating in the tract infections who visited 65 institutions located in 7 areas of Japan (shaded
Atypical Pathogen Study Group from January 2008 to December areas). (A) Kyushu; (B) Chugoku; (C) Shikoku; (D) Kinki; (E) Tokai; (F)
Kanto; (G) Hokkaido; (H) Hokuriku; (I) Koshinetsu; (J) Tohoku.
2012 were enrolled in this study. The coverage in each area was based
only on areas with collaborating physicians. Four areas (A, B, C, and
D) participated from 2008, area G participated from 2010, area E
participated from 2011, and area F participated from 2012. A com- pneumonia DNA was detected by real-time PCR targeting a con-
plete list of participating facilities is provided in the Acknowledg- served part of the gene coding for the P1 adhesin gene (14). A
ments. Nasopharyngeal swab specimens and sputum samples, if search for mutations at sites 2063, 2064, and 2617 in the M. pneu-
available, were collected from patients with RTIs by pediatricians at moniae 23S rRNA domain V gene region was performed using a
the facilities. Informed consent was obtained from the parents of all
patients, and the study protocol was approved by the Ethics Commit-
tee at Kawasaki Medical School. Received 1 April 2013 Returned for modification 27 April 2013
Cultivation of M. pneumoniae was carried out with pleuro- Accepted 16 May 2013
pneumonia-like organism broth (PPLO; Oxoid, Franklin, NJ) Published ahead of print 28 May 2013
supplemented with 0.5% glucose (Wako Pure Chemicals Inc., Address correspondence to Naoyuki Miyashita, nao@med.kawasaki-m.ac.jp.
Osaka, Japan), 20% mycoplasma supplement G (Oxoid), and Copyright © 2013, American Society for Microbiology. All Rights Reserved.
0.0025% phenol red (Sigma-Aldrich Co. LLC, St. Louis, MO) us- doi:10.1128/AAC.00663-13
ing sputum samples or nasopharyngeal swab specimens (14). M.

4046 aac.asm.org Antimicrobial Agents and Chemotherapy p. 4046 – 4049 August 2013 Volume 57 Number 8
 Surveillance of Macrolide-Resistant M. pneumoniae

TABLE 1 Prevalence of MR M. pneumoniae cases in seven areas of Japan and categorical variables for 561 pediatric patients with MR M.
pneumoniae infection
Result for the following area:
Variable A B C D E F G
No. of resistant cases/no. of M. pneumoniae-
infected patients (%)
2008 0/1 3/7 5/6 1/2 NDa ND ND
2009 1/3 5/6 0/1 3/3 ND ND ND
2010 18/21 (85) 27/35 (77) 6/6 3/17 (17) ND ND 25/31 (80)
2011 24/49 (49) 55/119 (46) 40/42 (95) 35/42 (83) 11/11 (100) ND 11/18 (61)
2012 19/27 (70) 106/124 (85) 10/10 (100) 68/77 (88) 76/92 (82) 9/18 (50) 0/1
5-yr total (2008–2012) 62/101 (61) 196/291 (67) 61/65 (93) 110/141 (78) 87/103 (84) 9/18 (50) 36/50 (72)

No. of patients 62 196 61 110 87 9 36

Mean (range) age (yr) 7.1 (0–14) 7.9 (0–15) 7.5 (0–14) 7.6 (1–15) 8.8 (3–15) 7.6 (3–13) 7.6 (2–3)
No. (%) of patients:

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⬍1 yr old 3 (5) 9 (5) 2 (3) 1 (1) 0 0 0
2–5 yr old 23 (37) 51 (26) 23 (38) 36 (33) 22 (25) 3 (33) 10 (28)
⬎6 yr old 36 (58) 136 (69) 36 (59) 73 (66) 65 (75) 6 (67) 26 (72)

No. of males/no. of females 31/31 113/83 36/25 55/55 39/48 5/4 18/18
No. (%) of disease cases
Pneumonia 36 (58) 116 (59) 41 (67) 76 (69) 58 (67) 5 (56) 23 (64)
Bronchitis 26 (42) 80 (41) 20 (33) 34 (31) 29 (33) 4 (44) 13 (36)

No. (%) of point mutations in domain V of

23S rRNA
A2063G 52 (84) 191 (98) 59 (96) 107 (97) 84 (97) 9 (100) 36 (100)
A2063T 10 (16) 4 (2) 1 (2) 3 (3) 0 0 0
A2063C 0 0 1 (2) 0 0 0 0
A2064G 0 1 (0.1) 0 0 2 (2) 0 0
C2617G 0 0 0 0 1 (1) 0 0

No. (%) of patients with prior prescription

Macrolides 22 (35) 101 (52) 51 (84) 79 (72) 73 (84) 4 (44) 22 (61)
Minocycline 0 3 (1) 0 1 (1) 0 0 0
Lincomycin 0 3 (1) 0 0 0 0 0
Tosufloxacin 3 (5) 14 (7) 0 1 (1) 1 (1) 0 0
␤-Lactams 14 (22) 28 (14) 4 (6) 4 (4) 5 (6) 0 7 (19)

No. (%) of patients treated with effective

antibiotics
Macrolides 14 (23) 28 (14) 7 (11) 15 (14) 7 (8) 3 (33) 14 (39)
Minocycline 18 (29) 118 (60) 34 (56) 31 (28) 52 (60) 1 (11) 6 (17)
Lincomycin 0 2 (1) 0 1 (1) 0 0 0
Tosufloxacin 30 (48) 48 (25) 20 (33) 63 (57) 28 (32) 5 (56) 16 (44)
␤-Lactams 0 0 0 0 0 0 0
a
ND, not determined.

direct sequencing method with isolates or samples with a positive
PCR result, as reported previously (3, 15, 16). The MICs of 11
antimicrobial agents for the isolates were determined by microdi-
lution methods (17). The antimicrobial agents used for MIC de-
termination were as follows: erythromycin, clarithromycin, azi-
thromycin, rokitamycin, clindamycin, minocycline, tetracycline,
tosufloxacin, garenoxacin, levofloxacin, and moxifloxacin.
Samples from a total of 2,120 patients with RTIs were sent to
Kawasaki Medical School Hospital. Of these, there were 769 cases
positive for M. pneumoniae by culture or real-time PCR. A total of
484 cases were classified as pneumonia, and the remaining 285
cases were classified as bronchitis. The prevalence of MR M. pneu-
moniae sequences in seven areas throughout Japan is shown in
Table 1. Five hundred sixty-one (73%) of 769 patients with M.
pneumoniae infection were determined to have a sequence for
MR. The resistance rate varied in each area, and the highest resis-
tance rate in 2012 was observed in area C, at 100%, and then in
area D at 88% and area B at 85%. In areas B and C, which both
have small populations, there were many patients with MR M.
pneumoniae. In contrast, in area F, there were few patients with
MR M. pneumoniae, although it is the most highly populated re-
gion in Japan. Figure 2 shows the year-by-year changes in the
prevalence of MR M. pneumoniae observed in all areas from 2008
to 2012. The frequency of MR genes increased gradually each year:
56% (9/16) in 2008, 69% (9/13) in 2009, 71% (79/110) in 2010,
63% (176/281) in 2011, and 82% (288/349) in 2012.

August 2013 Volume 57 Number 8 aac.asm.org 4047

Kawai et al.
FIG 2 Year-by-year increases in the frequency of macrolide-resistant Myco-
plasma pneumoniae cases from 2008 to 2012.
There was no significant difference in gender or disease classi-
fication between the seven surveillance areas, but the mean age
was significantly higher in area E than in area A (P ⫽ 0.0139)
(Table 1). The number of patients in the group ⬎6 years old was
significantly higher in area E than in area A (P ⫽ 0.0321), area B
(P ⫽ 0.0364), and area C (P ⫽ 0.0459). Among 561 patients with
MR M. pneumoniae, 538 had an A-to-G transition at position 2063
(A2063G), 18 had an A-to-T transition at position 2063 (A2063T),
3 had an A-to-G transition at position 2064 (A2064G), 1 had an
A-to-C transition at position 2063 (A2063C), and 1 had a C-to-G
transition at position 2617 (C2617G).
The prior prescription of antibiotics before visiting the study
clinic or hospital and the antibiotics effective against MR M. pneu-
moniae are shown in Table 1. Macrolides were administered to 352
(62%) patients before study enrollment (168 patients received cla-
rithromycin and 184 received azithromycin) and to 219 (39%)
patients after enrollment (121 patients received clarithromycin
and 98 received azithromycin). The resistance rate was closely
related to the previous administration of macrolides before visit-
ing the study clinic or hospital. The highest rates of prior prescrip-
tion of macrolides, at rates of 84%, were observed in areas C and E.
The resistance rates were 93% in area C and 84% in area E. The
majority of attending physicians treated patients with MR M.
pneumoniae with minocycline or tosufloxacin, in accordance with
the Japanese guidelines for the management of respiratory infec-
tious diseases in children (18).
A total of 252 isolates of M. pneumoniae were obtained by
cultivation of samples from these patients, and 183 isolates had a
mutation. The Japanese Society for Mycoplasmology has pro-
posed resistance breakpoints for the compounds employed
against M. pneumoniae isolates (19). The criteria for drug-resis-
tant M. pneumoniae are MICs of ⱖ16 ␮g/ml for erythromycin,
clarithromycin, and azithromycin. Among the 183 isolates of MR
M. pneumoniae, the MIC90 values for the 14- and 15-membered
macrolides erythromycin, clarithromycin, and azithromycin
were ⬎128 ␮g/ml, ⬎128 ␮g/ml, and 128 ␮g/ml, respectively,
which were higher than those for 69 macrolide-susceptible
(MS) M. pneumoniae isolates, with MIC90 values of 0.0078
␮g/ml for erythromycin, 0.0039 ␮g/ml for clarithromycin, and
0.0005 ␮g/ml for azithromycin. Conversely, tetracycline, mi-
4048 aac.asm.org
nocycline, tosufloxacin, garenoxacin, levofloxacin, and moxi-
floxacin showed good antimycoplasmal activity, with MIC90
values of 0.5 ␮g/ml, 2.0 ␮g/ml, 0.5 ␮g/ml, 0.0625 ␮g/ml, 0.5
␮g/ml, and 0.125 ␮g/ml, respectively, against MR M. pneu-
moniae isolates, which were equal to those against MS M. pneu-
moniae isolates. No regional differences in the drug suscepti-
bilities of the MR M. pneumoniae isolates were observed.
The increase in MR M. pneumoniae has become a serious issue
in Japan. M. pneumoniae pneumonia is specified for weekly re-
porting by specially designated sentinel clinics, in accordance with
the Japanese infectious diseases control law (1). However, most of
the reported cases with M. pneumoniae pneumonia are diagnosed
by serology and not culture or PCR. The National Institute of
Infectious Disease does not perform surveillance for mutations in
M. pneumoniae isolates. Thus, we carried out the first nationwide
surveillance of MR M. pneumoniae. The prevalence of MR M.
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pneumoniae is gradually increasing in pediatric patients. Although
regional differences were observed, high levels of MR genes were
detected in all areas of Japan, with the levels being 50 to 93% from
2008 to 2012. These regional differences were closely related to the
previous administration of macrolides.
It has been reported that more than half of attending physi-
cians felt that macrolides were clinically effective even in patients
infected with MR M. pneumoniae (3). Our previous study demon-
strated that 6 of 21 patients with MR M. pneumoniae infection
responded clinically to macrolide therapy (15). In addition, no
apparent treatment failure or serious illness was reported for pa-
tients with MR M. pneumoniae infection. Experimental and clin-
ical evidence supports the idea that the pathogenesis of lung
injuries caused by M. pneumoniae infection is associated with cell-
mediated immunity rather than with direct cell damage caused by
the pathogen itself (20–23). Numerous studies have documented
that certain macrolides have a wide spectrum of immunomodu-
latory effects on mammalian cells both in vivo and in vitro (24).
Thus, it is possible that the immunomodulatory effects of macro-
lides can improve clinical symptoms in these patients with MR M.
pneumoniae infection. It is important to determine the anti-in-
flammatory effect for the management of MR M. pneumoniae in-
fections. To evaluate the immunomodulatory effects, it will be
necessary to compare microbiological and clinical outcomes
among patients with MR M. pneumoniae infection treated or not
treated with macrolides.
Our study had several limitations. In some areas and years, the
number of patients was too low to clarify the prevalence of resis-
tance. In addition, not all areas participated simultaneously in the
epidemiological study. Consequently, this nationwide surveil-
lance program to investigate the prevalence of MR M. pneumoniae
cases will be continuing.
In conclusion, the prevalence of MR M. pneumoniae in Japa-
nese pediatric patients was very high, and regional differences
were observed. Physicians should evaluate patients for a history of
macrolide treatment before selecting antimicrobials.
ACKNOWLEDGMENTS
We thank Keiko Fujioka, Department of Pediatrics, Kawasaki Medical
School, for technical assistance.
This study was supported in part by MEXT KAKENHI (19591190 and
21591304) and project research grants from the Kawasaki Medical School
(13-401, 14-402, 15-405A, 16-405M, 17-402M, 18-401, 19-402M, 20-
4030).
Antimicrobial Agents and Chemotherapy

The individuals (facilities) participating in the Atypical Pathogen Study
Group and in the study were as follows: Hideki Asaki (Asaki Pediatric Clinic),
Kazutoyo Asada (National Mie Hospital), Tomohiro Ichimaru (Saga Prefec-
tural Hospital Koseikan), Toshio Ineda (Inada Clinic), Takuya Inoue (Chaya-
mati Pediatric Clinic), Masakazu Umemoto (Umemoto Pediatric Clinic),
Kanetsu Okura (Okura Clinic), Kenji Okada (Fukuoka National Hospital),
Takashige Okada (Okada Pediatric Clinic), Teruo Okafuji (Okafuji Pediatric
Clinic), Yasuko Okamoto (Okamoto Clinic), Shinichiro Oki (Higashisaga
National Hospital), Keiko Oda (Kawasaki Medical School Kawasaki Hospi-
tal), Jin Ochiai (Ochiai Pediatric Clinic), Seiko Obuchi (Obuchi Clinic), Yoji
Kanehara (Kanehara Pediatric Clinic), You Kanematsu (Kanematsu Pediat-
ric Clinic), Shoji Kouno (Shomonoseki City Central Hospital), Makoto
Kuramitsu (Aoba Pediatric Clinic), Katsuji Kuwakado (Kurashiki Central
Hospital), Satoshi Kuwano (Kuwano Kids Clinic), Tatuso Koga (Koga Pedi-
atric Clinic), Hayashi Komura (Komura Pediatric Clinic), Hiroshi Sakata
(Asahikawa-Kosei General Hospital), Takahisa Sakuma (Sakuma Pediatric
Clinic), Kazuhide Shiotsuki (Shiotsuki Internal Medicine Pediatric Clinic),
Yasushi Shimada (Shimada Clinic), Makio Sugita (Kurashiki Riverside Hos-
pital), Toru Sugimura (Sugimura Pediatric Clinic), Shumei Takeda (Takeda
Pediatric Clinic), Isao Tanaka (Mizushima Central Hospital), Hiroyuki
Tanaka (Tanaka Family Clinic), Naohumi Tomita (Tomita Clinic), Kensuke
Nagai (Nagai Pediatric Internal Medicine Clinic), Yoshikuni Nagao (Mabi
Memorial Hospital), Hidekazu Nakashima (Kojima Central Hospital), Ta-
dashi Nagata (Nagata Pediatric Clinic), Kimiko Nakamura (Enoura Clinic),
Kazuyo Nomura (Kama Red Cross Hospital), Kanoko Hashino (Hashino
Pediatric Clinic), Yuko Hirata (Hirata Internal Medicine Pediatric Clinic),
Kazumi Hiraba (Mokubo Pediatric Clinic), Takuji Fujisawa (Fujisawa Pedi-
atric Clinic), Akiko Maki (Hashima Pediatric Clinic), Toshinobu Matsuura
(Yoshino Pediatric Clinic), Nobuyoshi Mimaki (Kurashiki Medical Center),
Tatsuhiko Moriguchi (Sakai Hospital Kinki University Faculty of Medicine),
Shigeru Mori (Momotaro Clinic), Yoichiro Yamaguchi (Yamaguchi Pediat-
ric Clinic), Syuji Yamada (Yamada Pediatric Clinic), Teruyo Fujimi (Fujimi
Clinic), Norio Tominaga (Isahaya Health Insurance General Hospital),
Syunji Hasegawa (Yamaguchi University Graduate School of Medicine),
Kiyoko Nishimura (Nishimura Pediatric Clinic), Mihoko Mizuno (Daido
Clinic), Jiro Iwamoto (Iizuka Hospital), Toshiyuki Iizuka (Hakuai Hospital),
Shigeru Yamamoto (Daido Municipal Pediatric Clinic), Tomomichi Kura-
saki (Kurosaki Pediatric Clinic), and Tadashi Matsubayashi (Seirei
Hamamatsu General Hospital).
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