Abstract
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 regional 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.
TEXT
Mycoplasma 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 pediatric patients with pneumonia, and macrolide resistance has become 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 million people]; E, Tokai [15 million people]; F, Kanto [42 million people]; and G, Hokkaido [5 million people]; Fig. 1) participating in the Atypical Pathogen Study Group from January 2008 to December 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 complete list of participating facilities is provided in the Acknowledgments. Nasopharyngeal swab specimens and sputum samples, if available, were collected from patients with RTIs by pediatricians at the facilities. Informed consent was obtained from the parents of all patients, and the study protocol was approved by the Ethics Committee at Kawasaki Medical School.
Fig 1.
Samples were collected from pediatric patients with acute respiratory tract infections who visited 65 institutions located in 7 areas of Japan (shaded areas). (A) Kyushu; (B) Chugoku; (C) Shikoku; (D) Kinki; (E) Tokai; (F) Kanto; (G) Hokkaido; (H) Hokuriku; (I) Koshinetsu; (J) Tohoku.
Cultivation of M. pneumoniae was carried out with pleuropneumonia-like organism broth (PPLO; Oxoid, Franklin, NJ) supplemented with 0.5% glucose (Wako Pure Chemicals Inc., Osaka, Japan), 20% mycoplasma supplement G (Oxoid), and 0.0025% phenol red (Sigma-Aldrich Co. LLC, St. Louis, MO) using sputum samples or nasopharyngeal swab specimens (14). M. pneumonia DNA was detected by real-time PCR targeting a conserved part of the gene coding for the P1 adhesin gene (14). A search for mutations at sites 2063, 2064, and 2617 in the M. pneumoniae 23S rRNA domain V gene region was performed using a 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 microdilution methods (17). The antimicrobial agents used for MIC determination were as follows: erythromycin, clarithromycin, azithromycin, 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. pneumoniae 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 resistance 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 region 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.
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
| Variable | Result for the following area: |
||||||
|---|---|---|---|---|---|---|---|
| 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: | |||||||
| <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 |
| β-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) |
| β-Lactams | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
ND, not determined.
Fig 2.
Year-by-year increases in the frequency of macrolide-resistant Mycoplasma pneumoniae cases from 2008 to 2012.
There was no significant difference in gender or disease classification 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. pneumoniae are shown in Table 1. Macrolides were administered to 352 (62%) patients before study enrollment (168 patients received clarithromycin 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 visiting the study clinic or hospital. The highest rates of prior prescription 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 infectious 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 proposed resistance breakpoints for the compounds employed against M. pneumoniae isolates (19). The criteria for drug-resistant M. pneumoniae are MICs of ≥16 μg/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 μg/ml, >128 μg/ml, and 128 μg/ml, respectively, which were higher than those for 69 macrolide-susceptible (MS) M. pneumoniae isolates, with MIC90 values of 0.0078 μg/ml for erythromycin, 0.0039 μg/ml for clarithromycin, and 0.0005 μg/ml for azithromycin. Conversely, tetracycline, minocycline, tosufloxacin, garenoxacin, levofloxacin, and moxifloxacin showed good antimycoplasmal activity, with MIC90 values of 0.5 μg/ml, 2.0 μg/ml, 0.5 μg/ml, 0.0625 μg/ml, 0.5 μg/ml, and 0.125 μg/ml, respectively, against MR M. pneumoniae isolates, which were equal to those against MS M. pneumoniae isolates. No regional differences in the drug susceptibilities 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 reporting 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. 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 physicians felt that macrolides were clinically effective even in patients infected with MR M. pneumoniae (3). Our previous study demonstrated 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 patients with MR M. pneumoniae infection. Experimental and clinical 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 immunomodulatory effects on mammalian cells both in vivo and in vitro (24). Thus, it is possible that the immunomodulatory effects of macrolides can improve clinical symptoms in these patients with MR M. pneumoniae infection. It is important to determine the anti-inflammatory effect for the management of MR M. pneumoniae infections. 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 resistance. In addition, not all areas participated simultaneously in the epidemiological study. Consequently, this nationwide surveillance program to investigate the prevalence of MR M. pneumoniae cases will be continuing.
In conclusion, the prevalence of MR M. pneumoniae in Japanese 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).
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 Prefectural Hospital Koseikan), Toshio Ineda (Inada Clinic), Takuya Inoue (Chayamati 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 Hospital), Jin Ochiai (Ochiai Pediatric Clinic), Seiko Obuchi (Obuchi Clinic), Yoji Kanehara (Kanehara Pediatric Clinic), You Kanematsu (Kanematsu Pediatric 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 Pediatric 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 Hospital), 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), Tadashi 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 Pediatric 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 Pediatric 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 Kurasaki (Kurosaki Pediatric Clinic), and Tadashi Matsubayashi (Seirei Hamamatsu General Hospital).
Footnotes
Published ahead of print 28 May 2013
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